Senolytic cell-penetrating peptide compositions and uses

Abstract

The technology relates in part to compositions containing a cell-penetrating peptide that can be used to reduce a senescent cell population.

Description

[0001]ATTORNEY DOCKET: 05336.0005WO01 SENOLYTIC CELL-PENETRATING PEPTIDE COMPOSITIONS AND USES Cross-Reference to Related Applications This application is a non-provisional of, and claims priority to, U.S. Provisional PatentApplications 63 / 570,961 (filed March 28, 2024) and 63 / 656,349 (filed June 5, 2024), theentirety of which are incorporated by reference.Field The technology relates in part to compositions containing a cell-penetrating peptide that can be used to reduce a senescent cell population. Reference to a Sequence Listing This application contains a Sequence Listing in computer readable form. The computer readable form is incorporated herein by reference. The computer readable file is namedSequence.xml and was created on March 26, 2025 (34 kb).BackgroundSenescence is a process by which cells age and stop dividing but do not die. Over time apopulation of old, senescent cells can build up in tissues throughout the body of a subject.These cells remain active and can release harmful substances that may causeinflammation and damage to nearby non-senescent cells. Senescence may contribute todevelopment of cancer and other diseases. Production of proinflammatory molecules thatexist naturally in cells, including certain cytokines and chemokines, have been associatedwith senescence. The milieu of pro-inflammatory molecules related to aging and senescentcells is referred to as the senescence-associated secretory phenotype (SASP).SummaryCompositions containing certain components can reduce the rate of senescence. Acomponent that reduces an amount of pro-inflammatory molecules produced by cellsrelated to the senescence-associated secretory phenotype (SASP) is referred to as a“senomorphic”. A component that selectively eliminates senescent cells is referred to as a“senolytic”. Provided in certain aspects is a composition containing a senolytic cell-penetrating peptide (CPP) in an amount sufficient to reduce a senescent cell population,referred to as a “CPP composition.” In certain aspects, a CPP composition contains anactive ingredient containing, consisting essentially of, or consisting of the CPP. In certain ATTORNEY DOCKET: 05336.0005WO01aspects, a CPP composition contains a senomorphic component, which can be inassociation with the CPP in certain embodiments. In certain aspects, provided is a devicecontaining a CPP composition. In certain aspects, a CPP composition is used to reduce asenescent cell population. In certain aspects, provided is a method for determiningsenolytic cell reducing activity of a treatment administered to an aged animal, including anaged human. Certain implementations are described further in the following description,examples and claims, and in the drawings. Brief Description of the DrawingsThe drawings illustrate certain implementations of the technology and are not limiting. Forclarity and ease of illustration, the drawings are not made to scale and, in some instances,various aspects may be shown exaggerated or enlarged to facilitate an understanding ofparticular implementations. FIG.1A and FIG.1B show cytotoxicity curves of peptidesagainst proliferating and senescent cells. FIG. 2 illustrates an experimental scheme fortesting senolytic activity of peptides in an accelerated skin aging model in rats. FIG.3 shows beta-galactosidase staining of rat skin tissue, and FIG.4 shows quantification ofbeta-galactosidase staining of rat skin tissue. FIG. 5 illustrates an experimental scheme totest the senolytic activity of peptides in an accelerated systemic aging model in mice. FIG.6 shows representative SA-beta-gal-stained tissues and FIG.7 shows results fromquantification of % beta-gal+ area in the liver, kidneys, and spleen. FIG. 8, FIG. 9, and FIG.10 show representative p16 stained liver, spleen, and kidney, respectively, and FIG.11shows results from quantification of p16 MFI. FIG. 12 shows SA-beta-Gal % levels indifferent tissues of naturally aged mice. Detailed DescriptionDescribed herein are compositions containing a cell-penetrating peptide (CPP; referred toas “CPP compositions”) devices including a CPP composition and uses of CPPcompositions. Also described is a method for determining senolytic cell-reducing activity ofa treatment administered to an aged animal.CompositionsIn certain aspects, provided is a composition comprising, consisting essentially of, orconsisting of a senolytic cell-penetrating peptide (CPP) in an amount sufficient to reduce asenescent cell population. The senescent cell population can be (i) a beta-galactosidase- ATTORNEY DOCKET: 05336.0005WO01positive cell population; or (ii) a p16-positive cell population; or (iii) a urokinaseplasminogen activator receptor (uPAR)-positive cell population; or (iv) a combination of (i)and (ii); or (ii) and (iii); or (i) and (iii); or (i), (ii) and (iii). Beta-galactosidase and p16 arenaturally occurring proteins that can be expressed at a higher level in senescent cells thanin non-senescent cells (Valieva et al., Diagnostics12: 2309 (2022) Word Wide Web URLaddress doi.org / 10.3390 / diagnostics12102309). A p16 protein can be a p16INK4a protein.A CPP can contain naturally occurring amino acids. There are different amino acid isomers, and a CPP can contain D-amino acids, L-amino acids, or a combination of D-amino acids and L-amino acids. In certain embodiments, all amino acids of a CPP are L-amino acids orD-amino acids. A CPP in certain embodiments can contain a peptidomimetic portion andan amino acid portion. In certain instances a CPP is a peptidomimetic containing nonaturally occurring amino acids.A CPP sometimes contains about 50 or fewer amino acids, or about 45 or fewer aminoacids, or about 40 or fewer amino acids, or about 35 or fewer amino acids, or about 30 orfewer amino acids. Certain amino acids can have a net positive charge at pH 7.0(positively charged amino acid) or net negative charge at pH 7.0 (negatively chargedamino acid), and certain amino acids are hydrophobic or hydrophilic. Amino acids arereferred to herein by representative single-letter codes. Positively-charged amino acids atpH 7.0 include arginine (R), lysine (K) and histidine (H). Negatively-charged amino acids at pH 7.0 include aspartate (D) and glutamate (E). Hydrophilic amino acids include arginine (R), asparagine (N), aspartate (D), glutamine (Q), glutamate (E), histidine (H), lysine (K), serine (S) and threonine (T). Hydrophobic amino acids include glycine (G), alanine (A), leucine (L), isoleucine (I), valine (V), tryptophan (W), tyrosine (Y), phenylalanine (F), methionine (M), cysteine (C) and proline (P).A CPP can be an amphipathic peptide, and in certain embodiments a CPP has a netpositive charge at pH 7.0. In certain embodiments, a CPP contains hydrophilic aminoacids. A CPP contains positively-charged amino acids at pH 7.0 in certain embodiments,and a CPP can contain arginine (R) amino acids. In certain embodiments, the positively-charged amino acids are evenly distributed along the length of the peptide.In certain embodiments, a CPP contains hydrophobic amino acids, and a CPP can containleucine (L) amino acids, or alanine amino acids (A), or a combination of L amino acids andA amino acids. In certain embodiments, a CPP contains a greater proportion of ATTORNEY DOCKET: 05336.0005WO01hydrophobic amino acids than hydrophilic amino acids. A CPP in certain embodimentscontains a ratio of hydrophilic amino acids to hydrophobic amino acids at pH 7.0 of at leastabout 30:70 to about 40:60 or about 30:67 to about 40:60.In certain embodiments, a CPP contains one or more negatively-charged amino acids atpH 7.0, and a CPP can contain one or more glutamate (E) amino acids. In certainembodiments, a CPP contains at least two but no more than three negatively-chargedamino acids. In certain embodiments, a CPP contains a ratio of positively-charged aminoacids to negatively-charged amino acids of at least about 6:2 to about 9:2 or about 6:2 toabout 8:2. In certain embodiments, a ratio of R amino acids to E amino acids is at leastabout 6:2 to about 9:2 or about 6:2 to about 8:2.In certain embodiments, a CPP contains six or more R amino acids, twelve or more Aamino acids, and six or more L amino acids. In certain instances, a CPP contains two ormore segments containing RALA (SEQ ID NO: 1). In certain embodiments, a CPP containsEARLARALARALAR (SEQ ID NO: 2); or LARALARALRA (SEQ ID NO: 3); orEARLARALARALAR (SEQ ID NO: 2) and LARALARALRA (SEQ ID NO: 3). In certaininstances, a CPP contains X1-EARLARALARALARLARALARALRA-X3-EA (SEQ ID NO: 4),where: X1 is W or R. In certain instances, a CPP contains X1-EARLARALARALAR-X2-LARALARALRA-X3-EA (SEQ ID NO: 17), where X1 is W or R, X2 is selected from H or E;and X3 is C or R. In certain embodiments, a CPP contains an amino acid sequence at leastabout 80% or more identical to X1-EARLARALARALARLARALARALRA-X3-EA (SEQ IDNO: 4) and / or an amino acid sequence at least about 80% or more identical to X1-EARLARALARALAR-X2-LARALARALRA-X3-EA (SEQ ID NO: 17). In certain embodiments, a CPP contains: WEARLARALARALARHLARALARALRACEA (SEQ ID NO: 5).In certain embodiments, a CPP contains:WEARLARALARALARLARALARALRACEA (SEQ ID NO: 6); WEARLARALARALARLARALARALRACEA (SEQ ID NO: 7); WEARLARALARALARELARALARALRACEA (SEQ ID NO: 8); REARLARALARALARLARALARALRACEA (SEQ ID NO: 9); REARLARALARALARLARALARALRAREA (SEQ ID NO: 10); or REARLARALARALARELARALARALRAREA (SEQ ID NO: 11). ATTORNEY DOCKET: 05336.0005WO01 In certain embodiments, a CPP contains: GRKKRRQRRRPPPRKGGSRRNAWGNQSYAELISQAIESAPEKRLTL (SEQ ID NO: 12).In certain embodiments, a CPP contains: LLIILRRRIRKQAHAHSK (SEQ ID NO: 13),derived from murine VE-Cadherin and referred to as murine pVEC (“pVEC”), orLLIFLRRRLRKQARAHGK (SEQ ID NO: 14), derived from human VE-Cadherin andreferred to as a human pVEC (“hu-pVEC”).In certain embodiments, a CPP in a composition is in an amount sufficient to reduce asenescent cell population in vitro. In certain instances, a CPP in a composition is in anamount sufficient to reduce the senescent cell population in a tissue or organ. In certainembodiments, a CPP in a composition is in an amount sufficient to reduce the senescentcell population in a subject.A CPP composition can contain a particle containing a CPP, and a particle sometimes is ananoparticle. A particle can be a cell-penetrating nanoparticle. A nanoparticle can have a mean diameter of about 200 nanometers (nm) or less, or a mean diameter of about 150nm or less, or a mean diameter of about 100 nm or less, or a mean diameter of about 50nm or less.In certain embodiments, a CPP composition contains no cargo nucleic acid. A CPP often iscapable of associating with, and optionally encapsulating, another molecule, and the term“cargo” refers to a molecule associated with a CPP. In certain embodiments, a CPPcomposition contains no nucleic acid. In certain instances, a CPP composition contains nocargo component that reduces a senescent cell population. In certain embodiments, a CPPcomposition contains no component (for example, no cargo component) having one ormore of the following activities: (i) having JAK2 protein kinase inhibition activity; (ii) havingproinflammatory molecule reduction activity; (iii) having interleukin reduction activity (forexample, having IL-6 reduction activity); (iv) having senomorphic activity; or (v) a combination of (i) and (ii); (i) and (iii); (i) and (iv); (ii) and (iii); (ii) and (iv); (iii) and (iv); (i), (ii)and (iii); (i), (iii) and (iv); (ii), (iii) and (iv); or (i), (ii), (iii) and (iv). In certain instances, a CPPcomposition contains no cargo agent. In certain embodiments, a CPP composition containsno additive capable of reducing a senescent cell population. ATTORNEY DOCKET: 05336.0005WO01 In certain embodiments, a CPP composition contains an active ingredient, and the activeingredient contains, consists essentially of, or consists of the CPP. The term “consistsessentially of” with reference to an active ingredient containing a CPP means there is noother component in the active ingredient that materially affects the characteristics of the active ingredient. An active ingredient, for example, can include one or more componentsother than the CPP that enhance senescent cell population reduction activity by not morethan 5%. For example, an active ingredient can contain another component so long as the senescent cell population reduction activity of the active ingredient containing the CPP and other component is increased by no more than 5% compared to the active ingredientcontaining the CPP but not containing the other component. Senescent cell populationreduction activity of an active ingredient can be assessed by determining the amount of (i) beta-galactosidase; or (ii) p16 (p16INK4a for example); or (iii) urokinase plasminogen activator receptor (uPAR); or (iv) a combination of (i) and (ii); or (ii) and (iii); or (i) and (iii); or (i), (ii) and (iii). Senescent cell population reduction activity of an active ingredient can beassessed by a process described in Example 1, Example 2, Example 3, Example 4 orExample 6 herein.In certain embodiments, a CPP composition contains a separate senomorphic component.In certain instances, a CPP composition contains an active ingredient containing a CPP and a separate senomorphic component. A senomorphic component can be capable of reducing senescence-associated secretory phenotype (SASP) pro-inflammatory moleculesin cells. In certain instances, a senomorphic component reduces the amount of pro-inflammatory molecules such as cytokines and / or chemokines, and sometimes reduces theamount of interleukin (IL) molecules (IL-6 molecules for example). In certain embodiments,a senomorphic component is capable of inhibiting a JAK2 protein kinase. A senomorphiccomponent sometimes is negatively charged at pH 7.0. In certain instances, asenomorphic component has one or more of the following activities: (i) having JAK2 protein kinase inhibition activity; (ii) having proinflammatory molecule reduction activity; (iii) having interleukin reduction activity (for example, having IL-6 reduction activity); (iv) having senomorphic activity; or (v) a combination of (i) and (ii); (i) and (iii); (i) and (iv); (ii) and (iii); (ii) and (iv); (iii) and (iv); (i), (ii) and (iii); (i), (iii) and (iv); (ii), (iii) and (iv); or (i), (ii), (iii) and (iv). ATTORNEY DOCKET: 05336.0005WO01 In certain instances, a senomorphic component is a compound. In certain embodiments, acompound contains a quinazolinyl group and an amine-linked substituted phenyl group. Incertain instances, a compound is of Formula A:R3R13R2R4R129A thereof, where: R1, R2, R3, R4, R11, R12, R13, R14, R15, R16, R17and R18each independently is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 deuteroalkyl, optionally substituted C1-C6 alkylthio, optionally substituted C1-C6 alkylamino, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6mercaptoalkyl, optionally substituted C1-C6 aminoalkyl, RgC(O)N(Rh)-, -C(O)N(RgRh), -NRjRk, -C(O)Rz, -C(O)OH, -C(O)ORu, -B(OH)2, hydroxy, halo, nitro or cyano;R5, R6, R7, R8and R9each independently is hydrogen, optionally substituted C1-C6 alkyl, optionally C1-C6 alkoxy, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 deuteroalkyl, optionally substituted C1-C6 alkylthio, optionally substituted C1-C6 alkylamino, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 mercaptoalkyl, optionally substituted C1-C6 aminoalkyl, RpC(O)N(Rq)-, -C(O)N(RpRq), -NRrRs, -C(O)Rz, -C(O)OH, -C(O)ORu, -B(OH)2, hydroxy, halo, nitro or cyano; Rg, Rh, Rj, Rk, Rp, Rq, Rrand Rseach independently is hydrogen or optionally substituted C1-C6 alkyl;Rz is hydrogen or Ru; andRuis an optionally substituted C1-C6 alkyl. ATTORNEY DOCKET: 05336.0005WO01In certain embodiments, R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, R12, R13, R14, R15, R16, R17and R18each independently is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 deuteroalkyl, optionally substituted C1-C4 haloalkyl; optionally substituted C1-C4 alkylamino, halo or optionally substituted C1-C4 alkoxy. In certaininstances, R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, R12, R13, R14, R15, R16, R17 and R18 eachindependently is hydrogen, unsubstituted C1-C4 alkyl, Cl, F, CF3, CD3, unsubstituted C1- C4 alkoxy, methoxy, isopropyloxy or dimethylamino.In certain embodiments: (i) one, two, three or four of R1, R11, R12 and R13 each is hydrogen;(ii) one, two of three of R15, R17and R18each is hydrogen; (iii) one or two of R3and R4each is hydrogen;one, two, three or four of R5, R6, R8 and R9 each is hydrogen; and / or (iv) R2 is hydrogen. Incertain instances, R2is methyl, ethyl, methoxy or ethoxy, and R1, R3and R4each ishydrogen. In certain embodiments, R7 is -C(O)OH or -C(O)ORu. In certain embodiments,Ru is an optionally substituted C1-C4 alkyl, or ethyl or methyl. In certain embodiments, R7is RpC(O)N(Rq)- or -C(O)N(RpRq) and Rp and Rq each independently is hydrogen,optionally substituted C1-C4 alkyl, or ethyl or methyl. In certain instances, Rg, Rh, Rj, Rk,Rp, Rq, Rr and Rs each independently is hydrogen or methyl. In certain embodiments, (i)R14and R16each independently is hydrogen, unsubstituted C1-C4 alkyl, Cl, F, CF3, CD3, unsubstituted C1-C4 alkoxy, methoxy, isopropyloxy or dimethylamino; (ii) R14is unsubstituted C1-C4 alkoxy; (iii) R14is methoxy or isopropyloxy; (iv) R16is hydrogen,chloro or fluoro; and / or (v) R16 is hydrogen. In certain embodiments, a compound is ofFormula B: B or a Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to a parent moiety. The composite group alkylamido, for example, would ATTORNEY DOCKET: 05336.0005WO01 represent an alkyl group attached to a parent molecule through an amido group, the term amidoalkyl would represent an amido group attached to a parent molecule through an alkylgroup, the term alkylalkoxy would represent an alkyl group attached to a parent moleculethrough an alkoxy group, and the term alkoxyalkyl would represent an alkoxy group attached to a parent molecule through an alkyl group, for example. When a group is defined to be “null,” the group is absent. The term “optionally substituted” means the anteceding group may be substituted or unsubstituted. The term “substituted,” as used herein, refers, without limitation, to one or more substituents that can include, for example, substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower aryl, lower cycloalkyl, lower heteroaryl, lower heterocycloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, phenyl, aryloxy, lower hydroxyalkyl, lower mercaptoalkyl, lower aminoalkyl, lower arylaminoalkyl, aryloxyalkyl, lower aryloxyalkyl, arylthioalkyl, lower arylthioalkyl, heteroarylaminoalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, arylalkyl, lower arylalkyl, heteroarylalkyl, lower heteroarylalkyl, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3, CO2CH3, CO2H, B(OH)2, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Two substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic, heterocyclic aryl, or heteroaryl ring system having zero to three heteroatoms, for example, forming methylenedioxy or ethylenedioxy. An optionally substituted group may contain a deuterium in place of one or more hydrogen atoms (for example, -CD3 instead of -CH3). An optionally substituted group may be unsubstituted (for example, -CH2CH3), fully substituted (for example, -CF2CF3), monosubstituted (for example, -CH2CH2F) or substituted at a level anywhere in-between fully substituted and monosubstituted (for example, -CH2CF3). Where substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. Where a substituent is qualified as “substituted,” the substituted form is specifically intended. Additionally, different sets of optional substituents to a particular ATTORNEY DOCKET: 05336.0005WO01 moiety may be defined as needed. An optional substitution often is as defined, sometimes immediately following the phrase, “optionally substituted with.” The term R or the term R’, appearing by itself and without a number designation, unless otherwise defined, refers to a moiety chosen from hydrogen (H), alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted. Such R and R’ groups should be understood to be optionally substituted as defined herein. Whether an R group has a number designation or not, every R group, including R, R’ and Rnwhere n = (1, 2, 3, …n), every substituent, and every term should be understood to be independent of every other in terms of selection from a group. Should any variable, substituent, or term (for example aryl, heterocycle, R, etc.) occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence. Certain groups may be attached to a parentmolecule or may occupy a position in a chain of elements from either end as written. Thus,by way of example only, an asymmetrical group such as –C(O)N(R)– may be attached to aparent moiety at either the carbon or the nitrogen. In embodiments, the term ‘substituted’ and ‘substituent group’, as used herein, means a group selected from the following moieties:(A) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl,-CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2,-OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2,-NO2, -SH, -SO3H, –OSO3H, -SO2NH2, NHNH2, ONH2, NHC(O)NHNH2,NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3,-SF5, unsubstituted alkyl (for example, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (for example, 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (for example, C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (for example, 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (for example, C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (for example, 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and ATTORNEY DOCKET: 05336.0005WO01 (B) alkyl (for example, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (for example, 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (for example, C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (for example, 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (for example, C6-C10 aryl, C10 aryl, or phenyl), heteroaryl (for example, 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from:(i) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl,-CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2,-OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2,-NO2, -SH, -SO3H, –OSO3H, -SO2NH2, NHNH2, ONH2, NHC(O)NHNH2,NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3,-SF5, unsubstituted alkyl (for example, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (for example, 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (for example, C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (for example, 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (for example, C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (for example, 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (ii) alkyl (for example, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (for example, 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (for example, C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (for example, 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (for example, C6-C10 aryl, C10 aryl, or phenyl), heteroaryl (for example, 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from:(a) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl,-CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, - ATTORNEY DOCKET: 05336.0005WO01SO3H, –OSO3H, -SO2NH2, NHNH2, ONH2, NHC(O)NHNH2, NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3,-SF5, unsubstituted alkyl (for example, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (for example, 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (for example, C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (for example, 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (for example, C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (for example, 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (b) alkyl (for example, C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (for example, 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (for example, C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (for example, 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (for example, C6-C10 aryl, C10 aryl, or phenyl), heteroaryl (for example, 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituentselected from: oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2,-CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN,-OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, –OSO3H, -SO2NH2, NHNH2, ONH2,NHC(O)NHNH2, NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H,-NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (for example, C1-C8 alkyl, C1-C6 alkyl,or C1-C4 alkyl), unsubstituted heteroalkyl (for example, 2 to 8 membered heteroalkyl, 2 to 6membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (for example, C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (for example, 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (for example, C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (for example, 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). A “size-limited substituent” or “size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” ATTORNEY DOCKET: 05336.0005WO01 wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. A “lower substituent” or “lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted phenyl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 6 membered heteroaryl. In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In some embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In some embodiments, at least one or all of these groups are substituted with at least one lower substituent group. In some embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or ATTORNEY DOCKET: 05336.0005WO01 unsubstituted C6-C10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene. In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted orunsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below. In embodiments, a substituted or unsubstituted moiety (for example, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or ATTORNEY DOCKET: 05336.0005WO01 unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is unsubstituted (for example, is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and / or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (for example, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is substituted (for example, is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene, respectively). In embodiments, a substituted moiety (for example, substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent group, wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different. In embodiments, a substituted moiety (for example, substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one size-limited substituent group, wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different. In embodiments, if the substituted moiety is ATTORNEY DOCKET: 05336.0005WO01 substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different. In embodiments, a substituted moiety (for example, substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one lower substituent group, wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different. In embodiments, a substituted moiety (for example, substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group is different. The term “acyl,” as used herein, alone or in combination, refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety where the atom attached to the carbonyl is carbon. Non-limiting examples of acyl groups include formyl, alkanoyl and aroyl. An “acetyl” group refers to a –C(O)CH3 group. The term “aliphatic,” as used herein, refers to saturated and partially unsaturated, nonaromatic, straight chain (i.e., unbranched), branched and cyclic (including bicyclic and polycyclic) hydrocarbons which may be optionally substituted with one or more functional ATTORNEY DOCKET: 05336.0005WO01 groups. In certain embodiments, an aliphatic group contains 1 to 20 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 3 carbon atoms. An “alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached to a parent molecular moiety through a carbonyl group. Non-limiting examples of such groups include methylcarbonyl and ethylcarbonyl. The term “alkenyl,” as used herein, alone or in combination, refers to a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, an alkenyl includes 2 to 6 carbon atoms. The term “alkenylene” refers to a carbon-carbon double bond system attached at two or more positions such as ethenylene [(–CH=CH–),(–C::C–)]. Non-limiting examples of alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwise specified, the term “alkenyl” may include “alkenylene” groups. An alkene functionality is not directly bonded to a nitrogen. An alkenyl group containing an alkene functionality and alkyl portion, such as an allyl group, for example, can be bonded to a nitrogen such that the alkene functionality is not directly bonded to the nitrogen. The term “alkoxy,” as used herein, alone or in combination, refers to an alkyl ether radical, where the term alkyl is as defined below. Non-limiting examples of alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert- butoxy, and the like. The term “alkyl,” as used herein, alone or in combination, refers to a saturated straight- chain or branched-chain hydrocarbon radical containing from 1 to 20 carbon atoms. The term “straight-chain alkyl” refers to a saturated straight-chain hydrocarbon radical. The term “branched-chain alkyl” refers to a saturated branched-chain hydrocarbon radical. In certain embodiments, an alkyl includes 1 to 10 carbon atoms (C1-C10 alkyl), 1 to 8 carbon atoms (C1-C8 alkyl), 1 to 6 carbon atoms (C1-C6 alkyl) or 1 to 3 carbon atoms (C1-C3 alkyl). Alkyl groups may be optionally substituted as defined herein. Non-limiting examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, pentyl, iso-amyl, hexyl, octyl, nonyl and the like. The term “alkylene,” as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or ATTORNEY DOCKET: 05336.0005WO01 more positions, such as methylene (–CH2–). Unless otherwise specified, the term “alkyl” may include “alkylene” groups. The term “alkylamino,” as used herein, alone or in combination, refers to an alkyl group attached to a parent molecular moiety through an amino group. Alkylamino groups include monoalkylated groups (monoalkylamino) or dialkylated groups (dialkylamino), non-limiting examples of which include N-methylamino, N-ethylamino, N,N-dimethylamino, N,N- ethylmethylamino and the like. The term “alkylidene,” as used herein, alone or in combination, refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached. The term “alkylthio,” as used herein, alone or in combination, refers to an alkyl thioether (R–S–) radical where the term alkyl is as defined above and where the sulfur may be singly or doubly oxidized. Non-limiting examples of alkyl thioether radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like. The term “alkynyl,” as used herein, alone or in combination, refers to a straight-chain or branched chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, an alkynyl includes 2 to 6 carbon atoms. In some embodiments, an alkynyl includes 2 to 4 carbon atoms. The term “alkynylene” refersto a carbon-carbon triple bond attached at two positions such as ethynylene (–C:::C–, ––). Non-limiting examples of alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like. Unless otherwise specified, the term “alkynyl” may include “alkynylene” groups. An alkyne functionality is not directly bonded to nitrogen. An alkynyl group containing an alkyne functionality and an alkyl portion, such as a propargyl group, for example, can be bonded to a nitrogen such that the alkyne functionality is not directly bonded to the nitrogen. The terms “amido” and “carbamoyl,” as used herein, alone or in combination, refer to an amino group as described below attached to a parent molecular moiety through a carbonyl group, or vice versa. The term “C-amido” as used herein, alone or in combination, refers toa -C(O)N(RR’) group with R and R’ as defined herein or as defined by the specifically ATTORNEY DOCKET: 05336.0005WO01 enumerated “R” groups designated. The term “N-amido” as used herein, alone or incombination, refers to a RC(O)N(R’)- group, with R and R’ as defined herein or as definedby the specifically enumerated “R” groups designated. The term "acylamino" as used herein, alone or in combination, includes an acyl group attached to a parent moiety through an amino group. A non-limiting example of an "acylamino" group is acetylamino (CH3C(O)NH–). The term “amino,” as used herein, alone or in combination, refers to -NRR’, where R and R’ are independently chosen from hydrogen, alkyl, alkenyl, alkynyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. Additionally, R and R’ may combine to form heterocycloalkyl or heteroaryl, either of which may be optionally substituted. The term "aminoalkyl," as used herein, refers to an amino group attached to a parent molecule through an alkyl group (N(R)(R')-alkyl-), where R and R' are defined herein. The term "lower aminoalkyl," as used herein, refers to an amino group attached to a parent molecule through a lower alkyl group (N(R)(R')-lower alkyl-), where "lower alkyl," R and R' are defined herein. The term "aryl," as used herein, alone or in combination, refers to an aromatic cyclic ring system, or aromatic hydrocarbon ring system, in which all of the atoms that form the covalent structure of the one or more aromatic rings are carbon (referred to herein as an “aryl ring”). The aryl ring may be optionally substituted as defined herein. The ring system may be monocyclic or fused polycyclic, for example, bicyclic or tricylic (containing two or three rings fused together). In certain embodiments, the monocyclic aryl ring is C4-C10, or C5-C9, or C5-C8, or C5-C7, or, in certain embodiments, C5-C6, where these carbon numbers refer to the number of carbon ring member atoms that form the ring system. In some embodiments, the polycyclic ring system is a bicyclic aryl group, where the bicyclic aryl group in some embodiments is C8-C12, or, for example, C9-C10. In some embodiments, the polycyclic ring system is a tricyclic aryl group, where the tricyclic aryl group is C11-C18, or, for example, C12-C16. Non-limiting examples of aryl ring systems include phenyl (monocyclic, C6), naphthyl (bicyclic, C10), anthracenyl (tricyclic, C14) and phenanthryl (tricyclic, C14). ATTORNEY DOCKET: 05336.0005WO01 The term “arylalkenyl” or “aralkenyl,” as used herein, alone or in combination, refers to an aryl group attached to a parent molecular moiety through an alkenyl group. The term “arylalkoxy” or “aralkoxy,” as used herein, alone or in combination, refers to an aryl group attached to a parent molecular moiety through an alkoxy group. The term “arylalkyl” or “aralkyl,” as used herein, alone or in combination, refers to an aryl group attached to a parent molecular moiety through an alkyl group. The term “lower arylalkyl” or “lower aralkyl,” as used herein, alone or in combination, refers to a lower aryl group attached to a parent molecular moiety through a lower alkyl group, where "lower aryl" and "lower alkyl" are as defined herein. The term “arylalkynyl” or “aralkynyl,” as used herein, alone or in combination, refers to an aryl group attached to a parent molecular moiety through an alkynyl group. The term “arylalkanoyl” or “aralkanoyl” or “aroyl,” as used herein, alone or in combination, refers to an acyl radical derived from an aryl-substituted alkanecarboxylic acid, non-limiting examples of which include benzoyl, napthoyl, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like. The term "arylaminoalkyl" as used herein refers to an aryl group attached to a parent molecule through an aminoalkyl group (aryl-N(R)-alkyl-), where R is as defined herein. The term "lower arylaminoalkyl" as used herein refers to a lower aryl group attached to a parent molecule through a lower aminoalkyl group (lower aryl-N(R)-lower alkyl-), where "lower aryl," "lower aminoalkyl" and R are as defined herein. The term “aryloxy” as used herein, alone or in combination, refers to an aryl group attached to a parent molecular moiety through an oxygen atom. The term "aryloxyalkyl" as used herein refers to an aryl group attached to a parent molecule through an alkyl ether group (aryl-O-alkyl-). The term "lower aryloxyalkyl" as used herein refers to a lower aryl group attached to a parent molecule through a lower alkyl ether group (lower aryl-O-lower alkyl-), where "lower aryl" and "lower alkyl" are defined herein. The term "arylthioalkyl" as used herein refers to an aryl group attached to a parent molecule through a thioalkyl group (aryl-S-alkyl-). The term "lower arylthioalkyl" as used ATTORNEY DOCKET: 05336.0005WO01 herein refers to a lower aryl group attached to a parent molecule through a lower thioalkyl group (lower aryl-S-lower alkyl-) where "lower aryl" and "lower alkyl" are defined herein. The terms “benzo” and “benz,” as used herein, alone or in combination, refer to the divalent radical C6H4= derived from benzene. Non-limiting examples include benzothiophene and benzimidazole. The term "boronic acid" as used herein refers to a -B(OH)2 group. The term “carbamate,” as used herein, alone or in combination, refers to an ester of carbamic acid (–NHCOO–) which may be attached to a parent molecular moiety from either the nitrogen or acid end, and which may be optionally substituted as defined herein. The term “O-carbamyl” as used herein, alone or in combination, refers to a -OC(O)NRR’ group where R and R’ are as defined herein. The term “N-carbamyl” as used herein, alone or in combination, refers to aROC(O)NR’- group, where R and R’ are defined herein.The term “carbonyl,” as used herein, when alone includes formyl [–C(O)H] and incombination includes a –C(O)– group.The term “carboxyl” or “carboxy,” as used herein, refers to –C(O)OH or the corresponding “carboxylate” anion (for example, in a carboxylic acid salt). An “O-carboxy” group refers toa RC(O)O– group, where R is as defined herein. A “C-carboxy” group refers to a –C(O)ORgroup where R is as defined herein. The term “cyano,” as used herein, alone or in combination, refers to –CN. The terms “cycloalkyl,” and, interchangeably, “carbocycle,” as used herein, alone or in combination, refers to a ring system in which all of the ring member atoms are carbon and at least one of the rings is a saturated or partially unsaturated aliphatic cyclic ring moiety (referred to herein as a “cycloalkyl ring” or “carbocycle ring”). In some embodiments, each cyclic moiety contains from 3 to 12 carbon ring member atoms which may be optionally substituted as defined herein. In some embodiments, a cycloalkyl group contains 3 to 10 carbon ring member atoms. In certain embodiments, a cycloalkyl includes 5 to 7 carbon atoms. In certain embodiments, a cycloalkyl includes 5 to 6 carbon atoms. A cycloalkyl can be a monocyclic or polycyclic, for example, bicyclic or tricyclic, ring system in which at least one cyclic ring is a cycloalkyl ring. In certain embodiments, the monocyclic cycloalkyl ring is ATTORNEY DOCKET: 05336.0005WO01 C3-C10, or C5-C9, or C5-C8, or C5-C7, or, in certain embodiments, C5-C6, where these carbon numbers refer to the number of carbon ring member atoms that form the ring system. Polycyclic cycloalkyl ring systems include fused, bridged and spiro-fused rings. Polycyclic cycloalkyl ring systems as defined herein, include ring systems in which one or more cycloalkyl rings is / are fused to one or more aryl rings (benzo-fused cycloalkyl ring systems) and / or other cycloalkyl rings. In some embodiments, all of the rings in a polycyclic cycloalkyl ring system are cycloalkyl rings. In some embodiments, the polycyclic ring system is a bicyclic cycloalkyl group, where the bicyclic cycloalkyl group in some embodiments is C8-C12, or, for example, C9-C10. In some embodiments, the polycyclic ring system is a tricyclic cycloalkyl group, where the tricyclic cycloalkyl group is C11-C18, or, for example, C12-C16. Non-limiting examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, octahydronaphthalene, decahydronaphthalene, bicyclo[1,1,1]pentane and the like. Examples of aryl-fused cyclolalkyl ring systems include a benzene ring fused to hydrogenated or partially hydrogenated ring systems, non-limiting examples of which include dihydronaphthalene, tetrahydronaphthalene and indanyl. In polycyclic systems in which a cycloalkyl is fused to an aryl, attachment of the polycycle to the indicated point of attachment on the parent molecule may be through any ring atom of the polycycle rings. In some embodiments of polycyclic cycloalkyls, the polycycle is attached to the indicated point of attachment through a ring member atom of a cycloalkyl ring. In some embodiments of polycyclic cycloalkyls, the polycycle is attached to the indicated point of attachment through a ring member atom of a ring that is not a cycloalkyl ring, for example, an aryl ring. The term “carbocycle-alkyl” or “cycloalkylalkyl” as used herein, alone or in combination, refers to a carbocycle group attached to a parent molecular moiety through an alkyl group. The term “deuteroalkyl,” as used herein, alone or in combination, refers to an alkyl radical having the meaning as defined herein where one or more or all hydrogens are replaced with a deuterium. Specifically included are monodeuteroalkyl, dideuteroalkyl, trideuteroalkyl and polydeuteroalkyl radicals. A "lower deuteroalkyl" group is a C1-C6, C1-C5, C1-C4, C1- C3 or C1-C2 alkyl in which one or more hydrogens are replaced with a deuterium. A non- limiting example of a lower deuteroalkyl group is the trideuteroalkyl -CD3, in which the three hydrogens of -CH3 are replaced by deuterium. ATTORNEY DOCKET: 05336.0005WO01 The term “ester,” as used herein, alone or in combination, refers to a carboxy group bridging two moieties linked at carbon atoms. The term “ether,” as used herein, alone or in combination, refers to an oxy group bridging two moieties linked at carbon atoms. The term “halo,” or “halogen,” as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine. The term “haloalkoxy,” as used herein, alone or in combination, refers to a haloalkyl group attached to a parent molecular moiety through an oxygen atom. The term “haloalkyl,” as used herein, alone or in combination, refers to an alkyl radical having the meaning as defined above where one or more hydrogens are replaced with a halogen. Specifically included are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for example, sometimes include an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals sometimes include two or more of the same halo atoms or a combination of different halo radicals. Non-limiting examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.“Haloalkylene” refers to a haloalkyl group attached at two or more positions. Non-limitingexamples include fluoromethylene (–CFH–), difluoromethylene (–CF2 –), chloromethylene (–CHCl–) and the like. The term “heteroaliphatic,” as used herein, refers to an aliphatic moiety, as defined herein, that contains one or more heteroatoms, such as, for example, oxygen, nitrogen, sulfur, phosphorous and / or silicon, for example, in place of a carbon atom or between carbon atoms. In some embodiments, a heteroaliphatic group contains from one to three heteroatoms chosen from O, N, and S, and where the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. In certain embodiments, the heteroatom(s) may be placed at any interior position of the heteroaliphatic group. In some embodiments, up to two heteroatoms may be consecutive. In certain embodiments, a heteroaliphatic group includes 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 8 carbon atoms or 2 to 6 carbon atoms. ATTORNEY DOCKET: 05336.0005WO01 The term "heteroalkyl," as used herein, alone or in combination, refers to a saturated or unsaturated, stable straight or branched hydrocarbon chain having the stated number of carbon atoms and one or more heteroatoms, such as, for example, oxygen, nitrogen, sulfur, phosphorous and / or silicon, for example, in place of a carbon atom. In some embodiments, a heteroalkyl contains from one to three heteroatoms chosen from O, N, and S, and where the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. In certain embodiments, the heteroatom(s) maybe placed at any interior position of the heteroalkyl group. In some embodiments, up to twoheteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3. In certain embodiments, a heteroalkyl includes 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 8 carbon atoms or 2 to 6 carbon atoms. In some instances, a heteroalkyl contains from 1 to 3 degrees of unsaturation. Heteroalkyl groups may be optionally substituted as defined herein. The term “heteroalkenyl,” as used herein, alone or in combination, refers to an alkenyl moiety, as defined herein, that contains one or more heteroatoms, such as, for example, oxygen, nitrogen, sulfur, phosphorous and / or silicon, for example, in place of a carbon atom or between carbon atoms. In some embodiments, a heteroalkenyl contains from one to three heteroatoms chosen from O, N, and S, and where the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. In certain embodiments, the heteroatom(s) may be placed at any interior position of the heteroalkenyl group. In some embodiments, up to two heteroatoms may be consecutive. In certain embodiments, a heteroalkenyl includes 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 8 carbon atoms or 2 to 6 carbon atoms. The term “heteroalkynyl,” as used herein, alone or in combination, refers to an alkynyl moiety, as defined herein, that contains one or more heteroatoms, such as, for example, oxygen, nitrogen, sulfur, phosphorous and / or silicon, for example, in place of a carbon atom or between carbon atoms. In some embodiments, a heteroalkynyl contains from one to three heteroatoms chosen from O, N, and S, and where the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. In certain embodiments, the heteroatom(s) may be placed at any interior position of the heteroalkynyl group. In some embodiments, up to two heteroatoms may be consecutive. In ATTORNEY DOCKET: 05336.0005WO01 certain embodiments, a heteroalkynyl includes 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 8 carbon atoms or 2 to 6 carbon atoms. The term "heteroaryl," as used herein, alone or in combination, refers to a cyclic ringsystem in which at least one of the rings is an aromatic ring in which all ring member atomsare carbon, except for at least one heteroatom (referred to herein as a “heteroaryl ring”), such as, for example, nitrogen, oxygen and sulfur. The heteroaryl ring may be optionally substituted as defined herein. A heteroaryl can be a monocyclic or a fused polycyclic, for example, bicyclic or tricyclic, ring system in which at least one cyclic ring is an aromatic heteroaryl ring. Polycyclic, for example, bicyclic and tricyclic, fused heteroaryl ring systems as defined herein include heteroaryl ring systems in which one or more heteroaryl rings is / are fused to one or more aryl rings (which are referred to herein as aryl-fused heteroaryl rings), one or more cycloalkyl rings and / or one or more other heteroaryl rings. In some embodiments, all of the rings in a polycyclic heteroaryl ring system are heteroaryl rings. In certain embodiments, a heteroaryl ring contains at least one atom chosen from O, S, and N. In certain embodiments, a heteroaryl ring is a 3 to 15 membered monocyclic ring. In certain embodiments, a monocyclic heteroaryl group may contain from 4 to 10 ring member atoms, and may have, for example, 1 to 4 heteroatoms in the ring, where the remaining ring member atoms are carbon. In some embodiments, a bicyclic heteroaryl ring may contain from 8 to 15 ring member atoms, and have from 1 to 8 heteroatoms, where the remaining ring member atoms are carbon. In some embodiments, a tricyclic heteroaryl ring may contain from 11 to 18 ring member atoms, and have from 1 to 10 heteroatoms, where the remaining ring member atoms are carbon. Non-limiting examples of heteroaryls include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplary bicyclic and tricyclic heteroaryl groups include phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl,dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, and the like. In polycyclic systems inwhich a heteroaryl is fused to one or more rings that are not heteroaryl, attachment of the polycycle to the indicated point of attachment on the parent molecule may be through any ring member atom of the polycycle rings. In some embodiments of polycyclic heteroaryls, ATTORNEY DOCKET: 05336.0005WO01 the polycycle is attached to the indicated point of attachment through a ring member atom of a heteroaryl ring. In some embodiments of monocyclic or polycyclic heteroaryls, the monocyle or polycycle is attached to the indicated point of attachment through a ring member heteroatom of a heteroaryl ring. In some embodiments of polycyclic heteroaryls, the polycycle is attached to the indicated point of attachment through a ring member atom of a ring that is not a heteroaryl ring, for example, an aryl ring or a cycloalkyl ring. “Heteroaryl” includes sulfones, sulfoxides, N-oxides of tertiary nitrogen ring member atoms, and carbocyclic fused and benzo-fused ring systems. Non-limiting examples of a heteroaryl group may be referred to as an aryl group having one or more carbon atoms substituted with O, NRn, S, SO, SO2, where “n” denotes any positive integer. The term “heteroarylalkyl” as used herein, alone or in combination, refers to an unsubstituted or substituted heteroaryl group attached to a parent molecular moiety through an alkyl group. The term “lower heteroarylalkyl” as used herein, alone or in combination, refers to an unsubstituted or substituted lower heteroaryl group attached to a parent molecular moiety through a lower alkyl group where "lower heteroaryl" and "lower alkyl" are as defined herein. The term "heteroarylaminoalkyl" as used herein refers to a heteroaryl group attached to a parent molecule through an aminoalkyl group (heteroaryl-N(R)-alkyl-), where R is as defined herein. The term "lower heteroarylaminoalkyl" as used herein refers to a lower heteroaryl group attached to a parent molecule through a lower aminoalkyl group (lower heteroaryl-N(R)-lower alkyl-), where "lower heteroaryl," "lower alkyl" and R are as defined herein. The term "heteroaryloxyalkyl" as used herein refers to a heteroaryl group attached to a parent molecule through an alkyl ether group (heteroaryl-O-alkyl-). The term " lowerheteroaryloxyalkyl" as used herein refers to a lower heteroaryl group attached to a parentmolecule through a lower alkyl ether group (lower heteroaryl-O-lower alkyl-), where "lower heteroaryl" and "lower alkyl" are defined herein. The term "heteroarylthioalkyl" as used herein refers to a heteroaryl group attached to a parent molecule through a thioalkyl group (heteroaryl-S-alkyl-). The term "lower heteroarylthioalkyl" as used herein refers to a lower heteroaryl group attached to a parent molecule through a lower thioalkyl group (lower heteroaryl-S-lower alkyl-), where "lower heteroaryl" and "lower alkyl" are defined herein. ATTORNEY DOCKET: 05336.0005WO01 The term “heterocycle-alkyl” as used herein, alone or in combination, refers to a substituted or unsubstituted heterocycle group attached to a parent molecular moiety through an alkyl group. The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” or “heterocyclic” as used herein, alone or in combination, each refer to a ring system in which at least one of the rings is a saturated or partially unsaturated, heteroaliphatic, nonaromatic cyclic ring moiety in which all of the ring member atoms are carbon, except for at least one heteroatom (referred to herein as a “heterocycloalkyl ring,” “heterocycle ring” or “heterocyclic ring”). The one or more heteroatoms that can be in the ring include, for example, nitrogen, oxygen, sulfur, phosphorous and / or silicon. In some embodiments, the ring heteroatom or heteroatoms is selected from nitrogen, oxygen and sulfur. The heterocycloalkyl ring may be optionally substituted as defined herein. A heterocycloalkyl is a monocyclic or polycyclic, for example, bicyclic or tricyclic, ring system in which at least one cyclic ring is a heterocycloalkyl ring. Polycyclic heterocycloalkyl ring systems include fused, bridged and spiro-fused rings. Polycyclic heterocycloalkyl ring systems as defined herein, include ring systems in which one or more heterocycloalkyl rings is / are fused to one or more cycloalkyl, aryl, heteroaryl and / or heterocycloalkyl rings. In some embodiments, all of the rings in a polycyclic heterocycloalkyl ring system are heterocycloalkyl rings. In certain embodiments, a heterocycloalkyl includes 1 to 4 heteroatoms as ring member atoms. In some embodiments, a heterocycloalkyl moiety includes 1 to 2 heteroatoms as ring member atoms. In certain embodiments, a heterocycloalkyl moiety includes 3 to 8 ring member atoms in each ring. In some embodiments, a heterocycloalkyl moiety includes 3 to 7 ring member atoms in each ring. In yet some embodiments, a heterocycloalkyl moiety includes 5 to 6 ring member atoms in each ring. In some embodiments, a heterocycloalkyl can be a 3 to 15 membered nonaromatic ring, or a fused bicyclic, or tricyclic non-aromatic ring, which contains at least one atom chosen from O, S, and N. In certain embodiments, a monocyclic heterocycloalkyl or heterocycle group may contain from 4 to 10 ring member atoms, and may have, for example, 1 to 4 heteroatoms in the ring, where the remaining ring member atoms are carbon. In some embodiments, a bicyclic heterocycloalkyl or heterocycle group may contain from 8 to 15 ring member atoms, and have from 1 to 8 heteroatoms, where the remaining ring member atoms are carbon. In some embodiments, a tricyclic heterocycloalkyl or heterocycle group may contain from 11 to 18 ring member ATTORNEY DOCKET: 05336.0005WO01 atoms, and have from 1 to 10 heteroatoms, where the remaining ring member atoms are carbon. The term also includes fused polycyclic groups where one or more heterocyclic rings are fused with one or more cycloalkyl rings, aryl, heteroaryl and / or other heterocyclic groups. In polycyclic systems in which a heterocycloalkyl ring is fused to one or more rings that are not heterocycloalkyl, attachment of the polycycle to the indicated point of attachment on the parent molecule may be through any ring member atom of the polycycle rings. In some embodiments of polycyclic heterocycloalkyls, the polycycle is attached to the indicated point of attachment through a ring member atom of a heterocycloalkyl ring. In some embodiments of monocyclic or polycyclic heterocycloalkyls, the monocyle or polycycle is attached to the indicated point of attachment through a ring member heteroatom of a heterocycloalkyl ring. In some embodiments of polycyclic heterocycloalkyls, the polycycle is attached to the indicated point of attachment through a ring member atom of a ring that is not a heterocycloalkyl ring, for example, an aryl ring, heteroaryl ring or a cycloalkyl ring. “Heterocycloalkyl” and “heterocycle” include sulfones, sulfoxides and N-oxides of tertiary nitrogen ring member atoms. Non-limiting examples of heterocycle groups include aziridinyl, azetidinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, thiomorpholinyl, pyranyl, dihydropyridinyl, tetrahydropyridinyl, carabazolyl, xanthenyl, 1,3-benzodioxolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, isoindolinyl, dihydroisoindolyl and dihydroindolyl, and the like. The heterocycle groups may be optionally substituted unless specifically prohibited. Non-limiting examples of heterocycloalkyl groups may be referred to as cycloalkyl group having one or more carbon atoms substituted with O, NRn, S, SO, SO2, where n denotes any positive integer. The term “hydrazinyl” as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., –HN–NH–. The term “hydroxy,” as used herein, alone or in combination, refers to –OH. The term “hydroxyalkyl,” as used herein, alone or in combination, refers to a hydroxy group attached to a parent molecular moiety through an alkyl group. The term “lower hydroxyalkyl,” as used herein, alone or in combination, refers to a hydroxy group attached to a parent molecular moiety through a lower alkyl group, where "lower alkyl" is as defined herein. The term “imino,” as used herein, alone or in combination, refers to =N–. ATTORNEY DOCKET: 05336.0005WO01 The term “iminohydroxy,” as used herein, alone or in combination, refers to =N(OH) and =N–O–. The phrase “in the main chain” refers to the longest contiguous or adjacent chain of carbon atoms starting at the point of attachment of a group to the compounds of any one of the formulas disclosed herein. The term “isocyanato” refers to a –NCO group. The term “isothiocyanato” refers to a –NCS group. The phrase “linear chain of atoms” refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur. The term “lower,” as used herein, alone or in a combination, where not otherwise specifically defined, means a moiety containing from 1 to and including 6 carbon atoms. A "lower alkyl," for example, refers to an alkyl containing 1 to 6 carbon atoms (C1-C6), 1 to 5 carbon atoms (C1-C5), 1 to 4 carbon atoms (C1-C4), 1 to 3 carbon atoms (C1-C3), or 1 to 2 carbon atoms (C1-C2) (for example, an alkyl containing 1, 2, 3, 4, 5 or 6 carbon atoms; a C1, C2, C3, C4, C5 or C6 alkyl). The term “lower aryl,” as used herein, alone or in combination, means a C4-C6 aryl group, for example, a C5-C6 aryl group. A lower aryl group sometimes is a C4-C6 aryl ring group, or C5-C6 aryl ring group for example, including without limitation, phenyl. The term may also refer to a C8-C10 bicyclic ring aryl group, for example, including without limitation, napthyl. Lower aryl groups, including phenyl or napthyl, may be optionally substituted as provided. The term “lower heteroaryl,” as used herein, alone or in combination, means a four- membered, five-membered, or six-membered heteroaryl group. A lower heteroaryl group sometimes is (1) a monocyclic heteroaryl ring comprising five or six ring member atoms, of which between one and four of the ring member atoms may be heteroatoms chosen from O, S, and N, or (2) a bicyclic heteroaryl ring, where each of the fused rings comprises five or six ring member atoms, comprising between them one to four heteroatoms chosen from O, S, and N. Lower heteroaryl groups may be optionally substituted as provided. The term “lower cycloalkyl,” as used herein, alone or in combination, means a monocyclic cycloalkyl having between three and six ring member atoms. Non-limiting examples of ATTORNEY DOCKET: 05336.0005WO01 lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Lower cycloalkyl groups may be optionally substituted as provided. The term “lower heterocycloalkyl,” as used herein, alone or in combination, means a monocyclic heterocycloalkyl having between three and six ring member atoms, of which between one and four may be heteroatoms chosen from O, S, and N. Non-limiting examples of lower heterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyl groups may be optionally substituted as provided. The term “lower amino,” as used herein, alone or in combination, refers to -NRR’, where R and R’ are independently chosen from hydrogen, lower alkyl, and lower heteroalkyl, any of which may be optionally substituted. Additionally, the R and R’ of a lower amino group maycombine to form a five- or six-membered heterocycloalkyl, either of which may beoptionally substituted. The term "mercaptoalkyl," as used herein, refers to a mercaptan or mercaptyl group attached to a parent molecule through an alkyl group (-alkyl-SH), where R is defined herein. The term "lower mercaptoalkyl," as used herein, refers to a mercaptan or mercaptyl group attached to a parent molecule through a lower alkyl group, (-lower alkyl-SR), where "lower alkyl" and R are defined herein. The terms “mercaptyl” or “mercaptan” as used herein, alone or in combination, refers to an -SH group. The term “menthol,” as used herein, refers to 2-isopropyl-5-methylcyclohexanol. Menthol contains 3 chiral carbons and the term “menthol” encompasses all stereoisomers of the molecule unless specifically stated otherwise herein. For example, isomers of menthol include the (-)-menthol isomer ((1R, 2S, 5R)-2-isopropyl-5-methylcyclohexanol), (+)- menthol isomer ((1S, 2R, 5S)-2-isopropyl-5-methylcyclohexanol), (-)-isomenthol isomer ((1R, 2S, 5S)-2-isopropyl-5-methylcyclohexanol), (+)-isomenthol isomer ((1S, 2R, 5R)-2- isopropyl-5-methylcyclohexanol), (-)-neomenthol isomer ((1R, 2R, 5S)-2-isopropyl-5- methylcyclohexanol), (+)-neomenthol isomer ((1S, 2S, 5R)-2-isopropyl-5- methylcyclohexanol), (-)-neoisomenthol isomer ((1S, 2S, 5S)-2-isopropyl-5- methylcyclohexanol) and (+)-neoisomenthol isomer ((1R, 2R, 5R)-2-isopropyl-5- methylcyclohexanol). ATTORNEY DOCKET: 05336.0005WO01 The term “menthyl,” as used herein, refers to a radical derived from menthol. Typically, a menthyl radical can be linked to another chemical group through the oxygen atom of the menthyl group. The term “nitro,” as used herein, alone or in combination, refers to –NO2. The terms “oxy” or “oxa,” as used herein, alone or in combination, refer to –O–. The term “oxo,” as used herein, alone or in combination, refers to =O. The term “partially unsaturated,” as used herein, alone or in combination, refers to a straight-chain, branched-chain or ring moiety that includes at least one double or triple bond and that is not fully saturated. The term “partially unsaturated” when used in reference to a ring moiety means a ring having one or multiple sites of unsaturation but does not include aryl rings or heteroaryl rings as defined herein. The term “perhaloalkoxy” refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms. The term “perhaloalkyl” as used herein, alone or in combination, refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms. The term “piperitol,” as used herein, refers to p-menth-1-en-3-ol. Piperitol contains 2 chiral carbons and the term “piperitol” encompasses all stereoisomers of the molecule unless specifically stated otherwise herein. For example, isomers of piperitol include (3R, 4R)- piperitol (also referred to as trans-piperitol) and (3S, 4R)-piperitol (also referred to as cis- piperitol). The term “ring member atoms,” as used herein, refers to all of the atoms that form the covalent structure of a cyclic ring structure. By “saturated” is meant that the carbon-containing group contains no carbon-carbon double or triple bonds. The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein, alone or in combination, refer the –SO3H group and its anion as the sulfonic acid is used in salt formation. The term “sulfanyl,” as used herein, alone or in combination, refers to –S–. The term “sulfinyl,” as used herein, alone or in combination, refers to –S(O)–. ATTORNEY DOCKET: 05336.0005WO01 The term “sulfonyl,” as used herein, alone or in combination, refers to –S(O)2–.The term “N-sulfonamido” refers to a RS(=O)2NR’- group with R and R’ as defined herein.The term “S-sulfonamido” refers to a -S(=O)2NRR’, group, with R and R’ as defined herein.The terms “thia” and “thio,” as used herein, alone or in combination, refer to a –S– group oran ether where the oxygen is replaced with sulfur. The oxidized derivatives of the thio group, namely sulfinyl and sulfonyl, are included in the definition of thia and thio. The terms “thiol” and “mercapto”, as used herein, alone or in combination, refers to an –SH group. The term “thiocarbonyl,” as used herein, when alone includes thioformyl –C(S)H and incombination is a –C(S)– group.The term “N-thiocarbamyl” refers to an ROC(S)NR’– group, with R and R’ as definedherein. The term “O-thiocarbamyl” refers to a –OC(S)NRR’, group with R and R’ as defined herein. The term “thiocyanato” refers to a –CNS group.The term “trihalomethanesulfonamido” refers to a X3CS(O)2NR– group with X is a halogenand R as defined herein.The term “trihalomethanesulfonyl” refers to a X3CS(O)2– group where X is a halogen.The term “trihalomethoxy” refers to a X3CO– group where X is a halogen.The term “trisubstituted silyl,” as used herein, alone or in combination, refers to a silicone group substituted at its three free valences with groups as listed herein under the definition of substituted amino. Non-limiting examples include trimethylsilyl, tert-butyldimethylsilyl, triphenylsilyl and the like. The term “ureido,” as used herein, alone or in combination, refers to the univalent radicalNH2CONH– derived from urea. Non-limiting examples include ureidoproprionate andureidosuccinate.In certain embodiments, a senescent cell population reduced by a CPP compositioncontains skin cells, and the skin cells can include epidermis cells, dermis cells, orepidermis cells and dermis cells. In certain embodiments, a senescent cell populationreduced by a CPP composition contains systemic cells, and the systemic cells can include ATTORNEY DOCKET: 05336.0005WO01kidney cells, liver cells, spleen cells, or a combination thereof (kidney cells and liver cells;kidney cells and spleen cells; liver cells and spleen cells; or kidney cells, liver cells andspleen cells). In certain embodiments, a senescent cell population reduced by a CPPcomposition contains fibroblast cells. In certain embodiments, a CPP composition containsa senescent cell population in addition to a CPP, and sometimes a senescent cellpopulation contains one or more skin cells and / or system cells, including cell typesdescribed herein.In certain embodiments, a CPP composition contains particles, or nanoparticles, or cell-penetrating nanoparticles, which can be particles or nanoparticles described herein. Incertain embodiments, a CPP composition contains a skin-penetrating component, whichsometimes is a skin-penetrating ceramic. Non-limiting examples of skin-penetratingceramic devices are described in Tardors et al., Nature Medicine 26, 341-347 (2020); Wooet al., Journal of Controlled Release 361, 766-776 (2023).A CPP composition can be prepared as a pharmaceutically acceptable composition containing one or more pharmaceutically acceptable excipients, referred to as a CPPpharmaceutical composition. A CPP pharmaceutical composition can be prepared for asuitable route of administration, including topical or systemic administration, for example. Incertain embodiments, a CPP pharmaceutical composition is formulated as a topical cream.In certain instances, a CPP pharmaceutical composition is prepared for injection (forexample, for subcutaneous, intramuscular or intravenous administration). DevicesProvided in certain aspects is a device containing a CPP composition. In certainembodiments, a device is capable of transmitting a CPP composition into or through skin,which sometimes is skin of a subject. In certain embodiments, a CPP composition is provided with a separate device that does not include the CPP composition, where the CPP composition can be placed in the device for administration of the CPP composition. In certain embodiments, provided is a kit containing a CPP composition in a container. A kitcan be provided with or without a device for CPP composition administration. In certainembodiments, a device is provided that contains a CPP composition. A CPP composition sometimes is provided in unit dosage form. ATTORNEY DOCKET: 05336.0005WO01In certain instances, a device contains a needle. In certain instances, a device includesmultiple needles, which can be disposed in an array of needles. In certain embodiments, aneedle of a device is a microneedle. In certain embodiments, a device containing multipleneedles includes a patch on which the multiple needles are disposed. A patch sometimes is configured for direct application of the patch to skin of a subject, such that needlesdisposed on the patch contact the skin. In certain instances, a needle of a device is adissolvable microneedle. In certain instances, a CPP composition is disposed in a needleor needles of a device (within microneedles of a device for example). Non-limitingexamples of microneedle devices are described in Waghule et al., BiomedPharmacotherapy 109: 1249-1258 (2019); Chen, Advanced Drug Delivery Reviews 127:85-105 (2018) and Guillot et al., Pharmaceutics 12 (569): World Wide Web address URLdoi:10.3390 / pharmaceutics12060569 (2020), for example.In certain embodiments, a device including a needle or multiple needles contains a syringe. In certain instances, a device including a needle or multiple needles contains a componentconfigured for connection to a syringe. A needle or needles can be disposed on acomponent configured for connection to a syringe. A needle or needles in certainembodiments are integrated with a syringe component. In certain instances, a device thatcontains a needle or needles includes a syringe or is separate from a syringe. A non-limiting example of a device component containing multiple needles and can be connectedto a syringe is described in WO2014188429. A CPP composition sometimes is in an auto-injector device, which can include a spring-loaded syringe pre-filled with a CPPcomposition. An auto-injector device also is referred to as a pen device, and often is a one- use and disposable device. An auto-injector device often includes a cover that covers theneedle of the syringe, and often includes a pre-loaded spring as a power source, where thespring and associated mechanical components form a one-shot linear actuator. When triggered an actuator can drive a sequence that includes (i) accelerating the syringe forward, puncturing the injection site; (ii) actuating the piston of the syringe, injecting the pharmaceutical composition; and (iii) deploying a shield that covers the needle. Auto- injection devices are known and non-limiting examples for different pharmaceutical compositions include SureClick® auto-injector; Rebiject®, Rebiject II® and Rebidose® auto-injectors; Anapen®, EpiPen®, Emerade®, and Auvi-Q® auto-injectors; subcutaneous sumatriptan auto-injector. ATTORNEY DOCKET: 05336.0005WO01In certain embodiments, a device utilized in association with a CPP composition includesno needles. In certain instances, a device is capable of delivering an electric currentsufficient to inject a CPP composition into skin and / or through skin. In certainembodiments, a device is a patch that contains a CPP composition (for example, a patchcontaining no needle or needles). Such a patch can be contacted with skin of a subject,and a device capable of delivering an electric current can be associated with the patch (forexample, a device capable of delivering an electric current can contact the patch). A non-limiting example of a needleless device capable of delivering an electric current isdescribed in WO2006003659. A device not containing a needle can contain or beassociated with a CPP composition containing an agent that facilitates penetration of CPPs into or through skin, such as a CPP composition containing a cell-penetrating ceramic for example.Uses of compositions and devicesIn certain embodiments, a CPP composition is used to reduce a senescent cell population.In certain embodiments, provided is a method for reducing a senescent cell population,which includes administering a CPP composition to cells in an amount sufficient to reducethe senescent cell population. In certain embodiments, a CPP composition is used toreduce a senescent cell population in a tissue, organ or subject. In certain embodiments,provided is a method for reducing a senescent cell population, which includesadministering a CPP composition to a tissue, organ or subject in an amount sufficient toreduce the senescent cell population in the tissue, organ or subject. In certainembodiments, a CPP composition is used to treat a medical condition associated with asenescent cell population. In certain embodiments, provided is a method for treating amedical condition, which includes administering a CPP composition to a tissue, organ orsubject in an amount sufficient to reduce a senescent cell population in the subject.In certain instances, the cells, tissue, organ or subject contain, and optionally have beendetected to contain, a senescent cell population. Methods for detecting senescent cells areknown, including determining presence, absence and / or amount of (i) beta-galactosidase;or (ii) p16 (p16INK4a for example); or (iii) urokinase plasminogen activator receptor(uPAR); or (iv) a combination of (i) and (ii); or (ii) and (iii); or (i) and (iii); or (i), (ii) and (iii). Incertain embodiments, the senescent cell population is (i) a beta-galactosidase-positive cellpopulation; or (ii) a p16-positive cell population (a p16INK4a-positive cell population for ATTORNEY DOCKET: 05336.0005WO01example); or (iii) a urokinase plasminogen activator receptor (uPAR)-positive cellpopulation; or (iv) a combination of (i) and (ii); or (ii) and (iii); or (i) and (iii); or (i), (ii) and(iii). In certain embodiments, presence, absence and / or amount of a senescent cells in apopulation is detected in vitro, ex vivo and / or in vivo. In certain instances, presence,absence and / or amount of a senescent cells in a population is detected in a samplecontaining cells, tissue and / or organ of subject, and / or sometimes in a subject. In certainembodiments, a CPP composition is administered based on the presence, absence or amount of senescent cells detected.In certain embodiments, the senescent cell population contains skin cells, and the skincells sometimes include epidermis cells, dermis cells, or epidermis cells and dermis cells.In certain implementations, a CPP composition is administered to skin tissue (for example,skin tissue of a subject) topically or by injection. In certain embodiments, the senescent cellpopulation contains systemic cells, and sometimes the systemic cells include kidney cells,liver cells, spleen cells, or a combination thereof (described herein). In certainembodiments, a CPP composition is administered topically or by injection. In certainembodiments, a device described herein is used to administer a CPP composition, whichsometimes is for topical administration or administration by injection.In one embodiment, the senescent cell population is quantified. For example, an organ in an animal’s body is biopsied to obtain a cellular sample. In one embodiment, the animal is a human. The number or percentage of senescent cells in the cellular sample is determined. The number or percentage is correlated to statistical data for the animal’s species to determine a biologic age score (“Senescore”) for the animal. In this manner the biologic age score for the animal can be compared to the statistical data for the animal’s species and determine if the animal is experiencing an accelerated or diminished rate of aging.By way of illustration and not limitation, an individual’s skin may be biopsied and biologicage scored calculated based on the percentage of senescent cells in the biopsy. The individual may then be treated with one or more of the disclosed CPP compositions. After a predetermined period of time (e.g., at least 14 days, at least 30 days) the individual’s skin is biopsied again the individual’s biologic age score is recalculated to determine the efficacy of that therapy in reducing that individual’s biologic age. In one embodiment, the ATTORNEY DOCKET: 05336.0005WO01 percentage of senescent cells decreases over the predetermined period of time (i.e., the treatment recapitulates the cells) In one embodiment, two skin biopsies are taken from an individual person, one from a sun- exposed area of the skin and one from an area of the skin not exposed to the sun(reduced-sun-exposed) e.g., the buttocks or inguinal region). A biologic age score is thencalculated from each biopsy sample. A ratio of the two biologic age scores assesses whether the age of that individual’s skin is above or below their whole body biologic age score, as measured from the non-exposed skin. In some embodiments, the disclosed composites are applied topically only treat the skin. In some embodiments, punch biopsies of the skin are performed in multiple areas including both treated and untreated areas of the skin to assess the efficacy of the treatment by comparing biologic age scores obtained from treated and untreated areas. In some embodiments, the disclosed method treat the whole individual’s body, including the skin. Such embodiments may apply the conditions internally (e.g., injection such as IV injection) and also topically.In certain embodiments, a CPP composition has a detectable senolytic activity, andsometimes does not have a detectable senomorphic activity. In certain instances, a CPPcomposition has a detectable senomorphic activity, and sometimes a CPP composition hasa detectable senolytic activity and a detectable senomorphic activity. A senomorphicactivity and / or senolytic activity can be detected in vitro, ex vivo or in vivo as known.In certain embodiments, a medical condition treated by a CPP composition is actinickeratosis, Bowen’s disease, in situ carcinoma, atopic dermatitis, non-segmental vitiligo,psoriasis, ultraviolet (UV) damaged skin or aged skin. The UV damaged skin sometimes isseverely UV damaged skin, and sometimes the psoriasis is plaque psoriasis. In certaininstances, a medical condition is treated in a human subject. In some embodiments, the CPP composition is administered to treat a medical condition including delaying or preventing age-related disorders and maximizing healthy lifespan, infertility, lordokyphosis, sarcopenia, cataracts, fat loss, cardiac arrhythmias, arterial wall stiffening, impaired wound healing, dermal thinning (dermis and subdermal adipose layer thickness), physical fitness and exercise ability (e.g. time to exhaustion in a treadmill exercise test), amelioration of metabolic dysfunction and alleviation of age-related brain ATTORNEY DOCKET: 05336.0005WO01 inflammation and cognitive impairment. Examples of ameliorating metabolic disfunction include decreased fasting glucose levels and improved glucose tolerance when on a high- fat diet. This induces metabolic syndrome in even young animals fed a high fat diet. Metabolic syndrome is effectively reduced by elimination of senescent cells as measured by lower body weight, lower fasting blood glucose levels and improvements in both glucose and insulin tolerance. Also lower basal insulin levels after fasting that is followed by a significant increase in insulin levels 15 min after a glucose load in a Glucose Tolerance Test (GTT), indicative of improved pancreatic beta cell function. Further examples of chronic diseases and functional deficits in humans associated with advancing age, including but are not limited to: Table 1: Examples of targetable diseases due to gain-of-function mutations , , ATTORNEY DOCKET: 05336.0005WO01 CAG repeat Huntington 6066438 HTTCAG repeat Spinal and bulbar 313700 AR Table 2: Examples of targetable diseases due to loss-of-function mutations e ATTORNEY DOCKET: 05336.0005WO01 synthease deficiency Additional embodiments of the disclosed therapy can be used to target human diseases that are attributed to certain specific cell types. See Cornish et al, Exploring the cellularbasis of human disease through a large-scale mapping of deleterious genes to cell types,Genome Medicine (2015) 7:95. Examples of cell types include macrophages, monocyte- derived endothelial progenitor cell, (MDEPC), dendritic cell-MID, neutrophils, monocytes, T cells, Natural killer cells, lymphocyte of B lineage cells, migratory Langerhans cells, immature Langerhans cells, mesenchymal somatic cells, fat cells, skeletal muscle cells, myoblasts, mesenchymal precursor cells, tendon cells, chondrocyte cells, reticulocyte cells, mast cells, neuronal stem cells, neurons, astrocyte cells, hepatic stellate cells, chimeric antigen receptor (CAR)-T cells. Further examples of human diseases include osteoarthritis, macular degeneration, fatty liver, primary idiopathic dilated cardiomyopathy (PIDC), cardiomyopathy (hypertrophic), mental disorders, autistic disorders, bipolar disorders, tobacco use disorder, schizophrenia, ATTORNEY DOCKET: 05336.0005WO01 metabolic syndrome X, diabetes mellitus (type 2), coronary artery disease, atherosclerosis, myocardial infarction, coronary arteriosclerosis, coronary disease, giant cell arteritis, colitis (ulcerative), malaria (cerebral), diabetic nephropathies, cardiovascular diseases, pulmonary fibrosis, pneumonia, gingivitis, acute pancreatitis, subacute sclerosing panencephalitis (SSP), pancreatitis, periodontal diseases, glomerulonephritis (IgA), meningococcal infections, juvenile arthritis, leprosy, bacterial infections, silicosis, alopecia areata, spondylitis (ankylosing), lichen planus (oral), premature birth, graves ophthalmopathy, rhinitis (allergic, seasons), inflammatory bowel diseases, autoimmune diseases, psoriasis, hepatitis B (chronic), Sjogren’s syndrome, Sclerodermia (systemic) myasthenia gravis, atopy, mucocutaneous lymph node syndrome (MLNS), chronic periodontitis, periodontitis, pulmonary disease chronic obstructive (PDCO), multiple sclerosis, lupus erythematosus (systemic), graves disease, celiac disease, asthma, vitiligo, lupus vulgaris, lupus erythematosus (discoid), tuberculosis (pulmonary) malaria, hepatitis B, graft vs host disease, sarcoidosis, crohn disease, tuberculosis, hepatitis C, malaria (falciparum) Behcet syndrome, human immunodeficiency virus (HIV) infections, brucellosis, arthritis, arthritis (rheumatoid), arthritis (juvenile rheumatoid), severe acute respiratory syndrome (SARS), hepatitis C (chromic), preeclampsia. Osteoarthritis is considered an age-related disease and affects 14 % of people over the age of sixty. Chondrocytes are the cell type most significantly associated with osteoarthritis(q = 0.005), supporting the hypothesis that chondrocyte dysregulation is important to the development of the disease. Inflammation may occur as a result of this dysregulation. In one embodiment, the disclosed therapy targets chondrocytes to treat osteoarthritis patients. Preeclampsia is defined as the new onset of proteinuria and hypertension during the second half of pregnancy and affects 5–8 % of pregnancies. Fat cells have been identified as the cell type most strongly associated with preeclampsia (q = 0.059) supporting the hypothesis that adipocytes influence the development of the disease, possibly through the aberrant production of adipokines. In one embodiment, the disclosed therapy targets adipocytes to treat preeclampsia patients. Another embodiment, the disclosed compositions to administered to neuromuscular cells to provide long-lasting paralysis of their motor function. For example, the disclosed CPPcompositions may be administered to the glabellar complex, situated between the ATTORNEY DOCKET: 05336.0005WO01 eyebrows, to paralyze the muscle function and reduce the formation of wrinkles in the overlying skin.Additional embodiments of the disclosed composition administer the CPP compositions tocells with gain-of-function mutations or loss-of-function proteins with known allosteric activators (see Chen et al., Opportunities for developing therapies for rare genetic diseases: focus on gain-of function and allostery, Orphanet Journal of Rare Diseases (2017) 12:61) In certain embodiments, a CPP in a composition is administered at a dose of about 1mg / kg to about 10 mg / kg, or about 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg,8 mg / kg or 9 mg / kg. A CPP composition can be administered about one (1X) to about fivetimes (5X) weekly, or three times (3X) weekly, and in certain instances is administeredintraperitoneally, subcutaneously, intravenously or topically.Naturally aged animal model for assessing a senescent cell populationIn certain embodiments, provided is a method for assessing a senescent cell population inresponse to a treatment administered to an aged animal, including an aged human. Incertain implementations, an animal of a particular age is administered a treatment and aftera particular period of time after the treatment was first administered, a senescent cellpopulation in the animal is assessed. The age of the animal at which a treatment is firstadministered, referred to as an “initiation age,” can be selected such that there is asignificant senescent cell population in the animal, yielding a robust senescent cellpopulation signal when assessed. While the number of senescent cells typically expands inan animal as it ages, the cost of maintaining an animal also typically increases as ananimal ages. An animal can be selected for an initiation age at which (i) there is a sufficientsenescent cell population for assessment, while (ii) the cost of maintaining the animal isminimized, thereby resulting in a cost-effective and informative animal model for assessing a senescent cell population response to a treatment.In certain embodiments, an animal is a human animal. In other embodiments, the animalis a non-human animal, and sometimes is a rodent such as a mouse or rat. It has beendetermined for a rodent, such as a mouse, that an optimum initiation age for balancing arobust senescent cell population with maintenance cost is about 50 weeks to about 90weeks of age. In certain instances, an initiation age of an animal is about 60 weeks toabout 80 weeks, or about 60 weeks to about 75 weeks, or about 55 weeks to about 65 ATTORNEY DOCKET: 05336.0005WO01 weeks, or about 58 weeks to about 62 weeks, or about 60 weeks to about 70 weeks, or about 65 weeks to about 75 weeks, or about 70 weeks to about 80 weeks, or about 73 weeks to about 77 weeks, or about 74 weeks to about 76 weeks. In certain embodiments,an initiation age of an animal is about 50 weeks, about 51 weeks, about 52 weeks, about53 weeks, about 54 weeks, about 55 weeks, about 56 weeks, about 57 weeks, about 58 weeks, about 59 weeks, about 60 weeks, about 61 weeks, about 62 weeks, about 63 weeks, about 64 weeks, about 65 weeks, about 66 weeks, about 67 weeks, about 68weeks, about 69 weeks, about 70 weeks, about 71 weeks, about 72 weeks, about 73weeks, about 74 weeks, about 75 weeks, about 76 weeks, about 77 weeks, about 78 weeks, about 79 weeks, or about 80 weeks. In certain embodiments, an animal has naturally aged until the initiation age, and has notbeen administered a treatment prior to the initiation age that accelerates aging or increasesa senescent cell population. In certain embodiments, an animal naturally ages during andafter the initiation age and is not administered a treatment during or after the initiation agethat accelerates aging or increases a senescent cell population. For example, an animaloften is not administered a dose of radiation, such as gamma radiation or ultraviolet light(UV; UV-B light for example), prior to the initiation age, and often is not administered adose of radiation during or after the initiation age.In certain embodiments, a treatment includes administering a composition containing anactive ingredient to an animal. In certain instances, an active ingredient contains a CPP,and sometimes is a composition described herein. A composition can be administered atthe initiation age, and optionally one or more times after the composition is firstadministered over a period of time (referred to as a “treatment time period”). A senescentcell population can be assessed one or more times after a period of time has elapsed from when the composition is first administered (referred to as “an assessment time period”). A treatment time period and an assessment time period each independently can be about 1day to about 15 weeks, or about 1 week to about 5 weeks, or about 1 week to about 4weeks, or about 1 day, or about 2 days, or about 3 days, or about 4 days, or about 5 days,or about 6 days, or about 1 week, or about 2 weeks, or about 3 weeks, or about 4 weeks,or about 5 weeks, or about 6 weeks, or about 7 weeks, or about 8 weeks, or about 9weeks, or about 10 weeks, or about 11 weeks, or about 12 weeks, or about 13 weeks, orabout 14 weeks, or about 15 weeks. ATTORNEY DOCKET: 05336.0005WO01 In certain embodiments, a naturally occurring senescent cell population of an animal isassessed before, during and / or after a treatment is administered. In certain instances, noexogenous senescent cells are introduced to an animal before, during and / or after the firsttreatment is initiated. For example, no exogenous senescent cells, such as cells in a carrier(for example, in a gel carrier, in an alginate carrier) are introduced to an animal before,during and / or after the first treatment is initiated, in certain embodiments.In certain embodiments, a senescent cell population is assessed for a sample from ananimal. A sample often contains cells from an animal, and can contain a tissue or organfrom an animal. In certain embodiments, a senescent cell population is assessed in vitro orex vivo, sometimes before an animal has been sacrificed, and / or sometimes after ananimal has been sacrificed. In certain embodiments, a senescent cell population isassessed in vivo, such as by detecting a detectable molecule in association with senescentcells (detectable luciferase molecules for example).In certain embodiments, a senescent cell population is assessed by detecting presence,absence and / or amount of (i) beta-galactosidase; or (ii) p16 (p16INK4a for example); or (iii)urokinase plasminogen activator receptor (uPAR); or (iv) a combination of (i) and (ii); or (ii)and (iii); or (i) and (iii); or (i), (ii) and (iii). In certain embodiments, a senescent cellpopulation is in or from one or more of the following of an animal: brain, kidney, lung, liveror spleen. In certain instances, a senescent cell population is in or from brain of an animal,and sometimes is in or from one of the following of an animal: hippocampus, cerebralcortex, substantia nigra (compact part of substantia nigra for example), pallidum (dorsalregion of pallidum region for example). In naturally aged animals, such as mice forexample, the rate and magnitude of accumulation of senescent cells in the hippocampus isgreater than in the cerebral cortex, which can correlate with a greater incidence of age-related short-term memory decline compared to general cognitive decline that occurs with aging in humans. In certain embodiments, an initiation age of an animal is about 55 weeks to about 65 weeks, or about 58 weeks to about 62 weeks or about 60 weeks, and a senescent cell population in or from one of the following is assessed: kidney, lung, liver or spleen. In certain instances, an initiation age of an animal is about 55 weeks to about 65 weeks, orabout 58 weeks to about 62 weeks, or about 60 weeks, and a senescent cell population inor from cerebral cortex is assessed. In certain instances, an initiation age of an animal is ATTORNEY DOCKET: 05336.0005WO01about 70 weeks to about 80 weeks, or about 73 weeks to about 77 weeks, or about 75weeks, and a senescent cell population in or from hippocampus is assessed.Certain ImplementationsFollowing are non-limiting examples of certain implementations of the technology.A1. A composition, comprising a senolytic cell-penetrating peptide in an amount sufficient to reduce a senescent cell population. A2. The composition of embodiment A1, wherein the senescent cell population is (i) a beta- galactosidase-positive cell population; or (ii) a p16-positive cell population; or (iii) aurokinase plasminogen activator receptor (uPAR)-positive cell population; or (iv) acombination of (i) and (ii); or (ii) and (iii); or (i) and (iii); or (i), (ii) and (iii). A3. The composition of embodiment A1 or A2, wherein the cell-penetrating peptide contains about 50 or fewer amino acids. A4. The composition of any one of embodiments A1-A3, wherein the cell-penetrating peptide is an amphipathic peptide. A5. The composition of any one of embodiments A1-A4, wherein the cell-penetrating peptide has a net positive charge at pH 7.0. A6. The composition of any one of embodiments A1-A5, wherein the cell-penetrating peptide comprises hydrophilic amino acids. A7. The composition of any one of embodiments A1-A6, wherein the cell-penetrating peptide comprises positively-charged amino acids at pH 7.0. A8. The composition of embodiment A7, wherein the positively-charged amino acids comprise arginine (R) amino acids. A9. The composition of embodiment A7 or A8, wherein the positively-charged amino acids are evenly distributed along the length of the peptide. A10. The composition of any one of embodiments A1-A9, wherein the cell-penetrating peptide comprises hydrophobic amino acids. A11. The composition of embodiment A10, wherein the hydrophobic amino acids comprise leucine (L) amino acids, or alanine amino acids (A), or a combination of L amino acids and A amino acids. ATTORNEY DOCKET: 05336.0005WO01 A12. The composition of embodiment A10 or A11, wherein the cell-penetrating peptide comprises a greater proportion of hydrophobic amino acids than hydrophilic amino acids. A13. The composition of any one of embodiments A10-A12, wherein the cell-penetrating peptide comprises a ratio of hydrophilic amino acid residues to hydrophobic amino acid residues at pH 7.0 of at least about 30:70 to about 40:60 or about 30:67 to about 40:60. A14. The composition of any one of embodiments A1-A13, wherein the cell-penetrating peptide comprises one or more negatively-charged amino acids at pH 7.0. A15. The composition of embodiment A14, wherein the negatively-charged amino acids comprise a glutamate (E) amino acid. A16. The composition of embodiment A14 or A15, wherein the cell-penetrating peptide comprises at least two but no more than three negatively-charged amino acids. A17. The composition of any one of embodiments A7-A16 the ratio of positively-charged amino acids to negatively-charged amino acids is at least about 6:2 to about 9:2 or about 6:2 to about 8:2. A18. The composition of embodiment A17, wherein the ratio of R amino acids to E amino acids is at least about 6:2 to about 9:2 or about 6:2 to about 8:2. A19. The composition of any one of embodiments A15-A18, wherein the cell-penetratingpeptide comprises six or more R amino acids, twelve or more A amino acids, and six ormore L amino acids.A20. The composition of any one of embodiments A8-A19, wherein the cell-penetrating peptide comprises two or more segments comprising RALA (SEQ ID NO:1). A21. The composition of embodiment A20, wherein the cell-penetrating peptide comprises EARLARALARALAR (SEQ ID NO: 2); or LARALARALRA (SEQ ID NO: 3); or EARLARALARALAR and LARALARALRA. A22. The composition of embodiment A21, wherein the cell-penetrating peptide comprisesX1-EARLARALARALAR-X2-LARALARALRA-X3-EA (SEQ ID NO: 4), wherein: X1 is W or R;X2is optional and if present is selected from H or E; and X3is C or R, or an amino acid sequence at least about 80% or more identical to X1-EARLARALARALAR-X2-LARALARALRA-X3-EA (SEQ ID NO: 4). ATTORNEY DOCKET: 05336.0005WO01 A23. The composition of any one of embodiments A1-A22, wherein the cell-penetrating peptide comprises WEARLARALARALARHLARALARALRACEA (SEQ ID NO: 5). A23. The composition of any one of embodiments A1-A22, wherein the cell-penetrating peptide comprises: WEARLARALARALARLARALARALRACEA (SEQ ID NO: 6); WEARLARALARALARLARALARALRACEA (SEQ ID NO: 7); WEARLARALARALARELARALARALRACEA (SEQ ID NO: 8); REARLARALARALARLARALARALRACEA (SEQ ID NO: 9); REARLARALARALARLARALARALRAREA (SEQ ID NO: 10); or REARLARALARALARELARALARALRAREA (SEQ ID NO: 11). A24. The composition of any one of embodiments A1-A8, A10, A11 and A14-A16, wherein the cell-penetrating peptide comprises: GRKKRRQRRRPPPRKGGSRRNAWGNQSYAELISQAIESAPEKRLTL (SEQ ID NO: 12). A24.1. The composition of any one of embodiments A1-A8, A10, A11 and A14-A16, wherein the cell penetrating peptide comprises: LLIILRRRIRKQAHAHSK (SEQ ID NO: 13), or LLIFLRRRLRKQARAHGK (SEQ ID NO: 14). A25. The composition of any one of embodiments A1-A24.1, wherein the cell-penetrating peptide comprises D-amino acids, L-amino acids, or a combination of D-amino acids and L-amino acids. A25.1. The composition of any one of embodiments A1-A25, wherein the cell-penetrating peptide comprises a peptidomimetic portion or is a peptidomimetic. A26. The composition of any one of embodiments A1-A25.1, wherein the cell-penetrating peptide is in an amount sufficient to reduce the cell population in vitro. A27. The composition of any one of embodiments A1-A26, wherein the cell-penetrating peptide is in an amount sufficient to reduce the cell population in a tissue or organ. A28. The composition of any one of embodiments A1-A27, wherein the cell-penetrating peptide is in an amount sufficient to reduce the cell population in a subject. ATTORNEY DOCKET: 05336.0005WO01 B1. The composition of any one of embodiments A1-A28, comprising no cargo nucleic acid. B2. The composition of any one of embodiments A1-A28, comprising no nucleic acid. B3. The composition of any one of embodiments A1-A28, comprising no cargo agent that reduces the cell population. B4. The composition of any one of embodiments A1-A28, comprising no cargo agent. B5. The composition of any one of embodiments A1-A28, comprising no additive that reduces the cell population. B6. The composition of any one of embodiments A1-A28, wherein the composition comprises an active ingredient, and the active ingredient consists essentially of or consists of the cell-penetrating peptide. C1. The composition of any one of embodiments A1-A28, comprising a senomorphic component. C2. The composition of embodiment C1, wherein the senomorphic component is capable of inhibiting a JAK2 protein kinase. C3. The composition of embodiment C1 or C2, wherein the senomorphic component is a compound that is negatively charged at pH 7.0. C4. The composition of any one of embodiments C1-C3, wherein the compound comprises a quinazolinyl group and an amine-linked substituted phenyl group. C5. The composition of embodiment C4, wherein the compound is of Formula A: R3R13Formula A or a pharmaceutically acceptable salt, amide or ester thereof, where: ATTORNEY DOCKET: 05336.0005WO01 R1, R2, R3, R4, R11, R12, R13, R14, R15, R16, R17and R18each independently is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 deuteroalkyl, optionally substituted C1-C6 alkylthio, optionally substituted C1-C6 alkylamino, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6mercaptoalkyl, optionally substituted C1-C6 aminoalkyl, RgC(O)N(Rh)-, -C(O)N(RgRh), -NRjRk, -C(O)Rz, -C(O)OH, -C(O)ORu, -B(OH)2, hydroxy, halo, nitro or cyano;R5, R6, R7, R8and R9each independently is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 deuteroalkyl, optionally substituted C1-C6 alkylthio, optionally substituted C1-C6 alkylamino, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 mercaptoalkyl, optionally substituted C1-C6 aminoalkyl, RpC(O)N(Rq)-, -C(O)N(RpRq), -NRrRs, -C(O)Rz, -C(O)OH, -C(O)ORu, -B(OH)2, hydroxy, halo, nitro or cyano; Rg, Rh, Rj, Rk, Rp, Rq, Rrand Rseach independently is hydrogen or optionally substituted alkyl;Rz is hydrogen or Ru; andRuis an optionally substituted C1-C6 alkyl. C6. The compound of embodiment C5, where R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, R12, R13, R14, R15, R16, R17and R18each independently is hydrogen, optionally substituted C1- C4 alkyl, optionally substituted C1-C4 deuteroalkyl, optionally substituted C1-C4 haloalkyl; optionally substituted C1-C4 alkylamino, halo or optionally substituted C1-C4 alkoxy. C7. The compound of embodiment C5 or C6, where R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, R12, R13, R14, R15, R16, R17and R18each independently is hydrogen, unsubstituted C1-C4 alkyl, Cl, F, CF3, CD3, unsubstituted C1-C4 alkoxy, methoxy, isopropyloxy or dimethylamino. C8. The compound of any one of embodiments C5-C7, where: one, two, three or four of R1, R11, R12and R13each is hydrogen; one, two of three of R15, R17and R18each is hydrogen; one or two of R3and R4each is hydrogen; one, two, three or four of R5, R6, R8and R9each is hydrogen; and / or ATTORNEY DOCKET: 05336.0005WO01 R2is hydrogen. C9. The compound of any one of embodiments C5-C8, where R2is methyl, ethyl, methoxy or ethoxy, and R1, R3and R4each is hydrogen. C10. The compound of any one of embodiments C5-C9, where R7is -C(O)OH or - C(O)ORu. C11. The compound of any one of embodiments C5-C10, where R7is -C(O)OH. C12. The compound of any one of embodiments C5-C10, where Ruis an optionally substituted C1-C4 alkyl, or ethyl or methyl. C13. The compound of any one of embodiments C5-C12, where R7isRpC(O)N(Rq)- or -C(O)N(RpRq) and Rp and Rq each independently is hydrogen, optionallysubstituted C1-C4 alkyl, or ethyl or methyl. C14. The compound of any one of embodiments C5-C13, where Rg, Rh, Rj, Rk, Rp, Rq, Rrand Rseach independently is hydrogen or methyl. C15. The compound of any one of embodiments C5-C14, where (i) R14and R16each independently is hydrogen, unsubstituted C1-C4 alkyl, Cl, F, CF3, CD3, unsubstituted C1- C4 alkoxy, methoxy, isopropyloxy or dimethylamino; (ii) R14is unsubstituted C1-C4 alkoxy; (iii) R14is methoxy or isopropyloxy; (iv) R16is hydrogen, chloro or fluoro; and / or (v) R16is hydrogen. C16. The compound of any of embodiments C5-C15, which is of Formula B: B D1. The composition of any one of embodiments A1-A28, B1-B6 and C1-C16, wherein thecell population comprises skin cells. D2. The composition of embodiment D1, wherein the skin cells comprise epidermis cells, dermis cells, or epidermis cells and dermis cells. ATTORNEY DOCKET: 05336.0005WO01 D3. The composition of any one of embodiments A1-A28, B1-B6, C1-C16 and D1-D2, wherein the cell population comprises systemic cells. D4. The composition of embodiment D3, wherein the systemic cells comprise kidney cells, liver cells, spleen cells, or a combination thereof.D5. The composition of any one of embodiments A1-A28, B1-B6, C1-C16 and D1-D4,wherein the cell population comprises fibroblast cells.D6. The composition of any one of embodiments A1-A28, B1-B6, C1-C16 and D1-D5, comprising a cell population, which optionally is a senescent cell population. D7. The composition of any one of embodiments A1-A28, B1-B6, C1-C16 and D1-D6, comprising cell-penetrating nanoparticles. D8. The composition of embodiment D6, wherein the nanoparticles have a mean diameter of 200 nanometers or less. D9. The composition of any one of embodiments A1-A28, B1-B6, C1-C16 and D1-D8, comprising a skin-penetrating component. D10. The composition of embodiment D9, wherein the skin-penetrating component comprises a skin-penetrating ceramic. D11. The composition of any one of embodiments A1-A28, B1-B6, C1-C16 and D1-D10, formulated as a topical cream. E1. A device comprising a composition of any one of embodiments A1-A28, B1-B6, C1-C16 and D1-D11. E2. The device of embodiment E1, which is capable of transmitting the composition into or through skin. E3. The device of embodiment E2, comprising a needle. E4. The device of embodiment E3, comprising multiple needles, optionally disposed in an array of needles. E5. The device of embodiment E3 or E4, wherein each needle is a microneedle. E6. The device of embodiment E5, wherein each needle is a dissolvable microneedle. E7. The device of any one of embodiments E1-E6, comprising a syringe. ATTORNEY DOCKET: 05336.0005WO01 E8. The device of embodiment E1 or E2, comprising no needles. E9. The device of embodiment E8, capable of delivering an electric current sufficient to inject the composition into skin and / or through skin. F1. A method for reducing a senescent cell population, comprising administering acomposition comprising an active ingredient comprising a cell-penetrating peptide to cellsin an amount sufficient to reduce the senescent cell population. F2. A method for reducing a senescent cell population, comprising administering a composition comprising an active ingredient comprising a cell-penetrating peptide to atissue, organ or subject in an amount sufficient to reduce a senescent cell population.F3. A method for treating a medical condition, comprising administering a composition comprising an active ingredient comprising a cell-penetrating peptide to a tissue, organ or subject in an amount sufficient to reduce a senescent cell population. F4. The method of any one of embodiments F1-F3, wherein the cells, tissue, organ or subject contain a senescent cell population. F5. The method of any one of embodiments F1-F4, wherein the senescent cell population is (i) a beta-galactosidase-positive cell population; or (ii) a p16-positive cell population; or(iii) a urokinase plasminogen activator receptor (uPAR)-positive cell population; or (iv) acombination of (i) and (ii); or (ii) and (iii); or (i) and (iii); or (i), (ii) and (iii). F6. The method of any one of embodiments F1-F5, wherein the senescent cell population comprises skin cells. F7. The method of embodiment F6, wherein the skin cells comprise epidermis cells, dermis cells, or epidermis cells and dermis cells. F8. The method of any one of embodiments F1-F7, wherein the senescent cell population comprises systemic cells. F9. The method of embodiment F8, wherein the systemic cells comprise kidney cells, liver cells, spleen cells, or a combination thereof. F10. The method of any one of embodiments F1-F9, wherein the composition is of any one of embodiments A1-A28 and D1-D11. ATTORNEY DOCKET: 05336.0005WO01 F11. The method of any one of embodiments F1-F10, wherein the composition is of any one of embodiments B1-B6 and D1-D11. F12. The method of any one of embodiments F1-F10, wherein the composition has senomorphic activity. F13. The method of embodiment F12, wherein the composition comprises a senomorphic component. F14. The method of embodiment F12 or F13, wherein the composition is of any one of embodiments C1-C16 and D1-D11. F15. The method of any one of embodiments F1-F14, using a device of any one of embodiments E1-E9. F16. The method of any one of embodiments F3-F15, wherein the medical condition is actinic keratosis, Bowen’s disease, in situ carcinoma, atopic dermatitis, non-segmental vitiligo, psoriasis, ultraviolet (UV) damaged skin or aged skin. F17. The method of embodiment F16, wherein the UV damaged skin is severely UV damaged skin. F19. The method of embodiment F17, wherein the psoriasis is plaque psoriasis.F20. The method of any one of embodiments F1-F19, wherein the composition comprisesabout 1 mg / kg to about 10 mg / kg of the cell penetrating peptide.F21. The method of embodiment F20, wherein the composition comprises about 5 mg / kg of the cell penetrating peptide. F22. The method of any one of embodiments F1-F21, wherein the composition isadministered about one (1X) to about five times (5X) per week.F23. The method of embodiment F22, wherein the composition is administered about threetimes per week. F24. The method of any one of embodiments F1-F23, wherein the composition is administered intraperitoneally, subcutaneously, intravenously or topically. G1. A method for assessing a senescent cell population of an animal, comprising: (i) administering a treatment to an animal at an initiation age, and (ii) after a period of time has elapsed from (i), assessing a senescent cell population of the animal. ATTORNEY DOCKET: 05336.0005WO01 G2. The method of embodiment G1, wherein the animal is a rodent. G3. The method of embodiment G2, wherein the rodent is a mouse. G4. The method of any one of embodiments G1-G3, wherein the initiation age is about 50 weeks to about 90 weeks, or optionally about 60 weeks to about 80 weeks, optionally about 60 weeks to about 75 weeks, optionally about 55 weeks to about 65 weeks, optionally about 58 weeks to about 62 weeks, optionally about 60 weeks to about 70 weeks, optionally about 65 weeks to about 75 weeks, optionally about 70 weeks to about 80 weeks, optionally about 73 weeks to about 77 weeks, or optionally about 74 weeks to about 76 weeks. G5. The method of any one of embodiments G1-G4, wherein the animal has naturally aged until the initiation age. G6. The method of embodiment, G5, wherein the animal has not been administered a treatment prior to the initiation age that accelerates aging or increases a senescent cell population. G7. The method of any one of embodiments G1-G6, wherein the animal naturally ages during and after the initiation age. G8. The method of embodiment G7, wherein the animal is not administered a treatment during or after the initiation age that accelerates aging or increases a senescent cell population. G9. The method of any one of embodiments G5-G8, wherein the animal is not administered radiation prior to, during and / or after the initiation age. G10. The method of embodiment G9, wherein the radiation is gamma radiation or ultraviolet light. G11. The method of any one of embodiments G1-G10, wherein the treatment comprises administering a composition containing an active ingredient to the animal. G12. The method of embodiment G11, wherein the active ingredient comprises a cell- penetrating peptide. G13. The method of embodiment G12, wherein the composition is of any one of embodiments A1-A28, B1-B6, C1-C16 and D1-D11. ATTORNEY DOCKET: 05336.0005WO01 G14. The method of any one of embodiments G11-G13, wherein the composition is administered using a device of any one of embodiments E1-E9. G15. The method of any one of embodiments G11-G14, wherein the composition is administered one or more times after (i) in a treatment time period. G16. The method of embodiment G15, wherein the treatment time period is about 1 day to about 15 weeks, or optionally about 1 week to about 5 weeks, or optionally about 1 week to about 4 weeks. G17. The method of any one of embodiments G1-G16, wherein a naturally occurring senescent cell population of the animal is assessed before, during and / or after a treatment is administered. G18. The method of embodiment G17, wherein no exogenous senescent cells are introduced to the animal before, during and / or after the first treatment is initiated. G19. The method of any one of embodiments G1-G18, wherein the senescent cell population is assessed one or more times after (i) in an assessment time period. G20. The method of embodiment G19, wherein the assessment time period each independently is about 1 day to about 15 weeks, or optionally about 1 week to about 5 weeks, or optionally about 1 week to about 4 weeks. G21. The method of any one of embodiments G1-G20, wherein the senescent cell population is assessed for a sample from the animal. G22. The method of embodiment G21, wherein the sample contains cells from the animal, optionally contains a tissue from the animal or optionally contains an organ from the animal. G23. The method of any one of embodiments G1-G22, wherein the senescent cell population is assessed in vitro or ex vivo. G24. The method of any one of embodiments G1-G23, wherein the senescent cell population is assessed in vivo. G25. The method of any one of embodiments G1-G24, wherein the senescent cell population is assessed before and / or after the animal has been sacrificed. ATTORNEY DOCKET: 05336.0005WO01 G26. The method of any one of embodiments G1-G25, wherein the senescent cell population is assessed by detecting presence, absence and / or amount of (i) beta- galactosidase; or (ii) p16 (p16INK4a for example); or (iii) urokinase plasminogen activator receptor (uPAR); or (iv) a combination of (i) and (ii); or (ii) and (iii); or (i) and (iii); or (i), (ii) and (iii). G27. The method of any one of embodiments G1-G26, wherein a senescent cell population is in or from one or more of the following tissues of the animal: brain, kidney, lung, liver and spleen. G28. The method of embodiment G27, wherein the senescent cell population is in or from brain of an animal, and optionally is in or from one of the following tissues of an animal: hippocampus, cerebral cortex, substantia nigra and pallidum. G29. The method of embodiment G28, wherein the senescent cell population is in or from the substantia nigra, and optionally is in or from a compact part of the substantia nigra, and / or is in or from the pallidum, and optionally is in or from a dorsal region of the pallidum region. G30. The method of any one of embodiments G1-G29, wherein the initiation age of the animal is about 55 weeks to about 65 weeks, or optionally about 58 weeks to about 62 weeks, or optionally about 60 weeks, and a senescent cell population in or from one of the following tissues is assessed: kidney, lung, liver or spleen. G31. The method of any one of embodiments G1-G30, wherein the initiation age of the animal is about 55 weeks to about 65 weeks, or optionally about 58 weeks to about 62 weeks, or optionally about 60 weeks, and a senescent cell population in or from cerebral cortex tissue of the animal is assessed. G32. The method of any one of embodiments G1-G29, wherein the initiation age of the animal is about 70 weeks to about 80 weeks, or optionally about 73 weeks to about 77 weeks, or optionally about 75 weeks, and a senescent cell population in or from hippocampus tissue of the animal is assessed. ExamplesThe examples set forth below illustrate certain implementations and do not limit thetechnology. ATTORNEY DOCKET: 05336.0005WO01 Example 1: Cell penetrating peptide senolytic activity in fibroblasts Senolytic activity of peptides was assessed in an in vitro fibroblast accelerated-aging model. On Day 0, IMR-90 human fetal lung fibroblasts were plated in tissue culture (TC)- treated flasks and adhered overnight. To induce senescence, cells were exposed to 10 grays (Gy) of ionizing gamma-irradiation on Day 1. Cells were kept in culture from Days 2- 8 as both a recovery period and to allow cells to enter a senescent state. Cellular senescence was confirmed by senescence-associated beta-galactosidase staining (SA- beta-gal). On Day 9, various test peptides (Table 1 of this Example) and controls were titrated onto senescent IMR-90 fibroblasts and, as a control for senolytic activity, proliferating IMR-90 fibroblasts. Test peptides and control peptides were added to cells starting at 100 micromolar (µM) along with additional half-log dilutions down to 3.16 nanomolar (nM). Cells were then incubated in the presence of peptides for a total of 5 days. Three days after initial addition of peptides (Day 12 of the assay), media was replaced with fresh media and peptides. Table 1. Peptide amino acid sequences Peptide Sequence (N to C)*L acids. On the final day of the assay, Day 14, cell viability was analyzed using the CellTiter-Glo® luminescent viability assay (Promega). Relative cell viability was normalized to the lowest peptide concentration and relative viability values were calculated. Relative viability values were then plotted and EC50 values calculated using GraphPad Prism Software. FIG.1A and FIG.1B show plots of relative viability and Table 2 of this Example shows the calculated EC50 values of four peptides analyzed using this cytotoxicity assay. The x-axis of FIG.1A and FIG.1B is cell-penetrating peptide concentration, designated as “[CPP].” P1 showed senolytic activity, while P2 had an EC50 value twice as high in healthy, proliferating cells than that observed in senescent cells. P1 was considered a relatively specificsenolytic CPP according to the study. FIG. 1A and FIG. 1B depict cytotoxicity curves ofpeptides against proliferating and senescent cells. ATTORNEY DOCKET: 05336.0005WO01 Table 2. Summary of EC50 Values from proliferating and senescent IMR-90 sells treated with peptides EC50 (µM) Peptide Proliferating Senescent Senolytic activity of peptides was assessed by an accelerated skin aging model in rats. Male CD-IGS (Sprague Dawley) rats (4-weeks old at study initiation) were exposed to a total of 20,000 mJ / cm2of UVB irradiation 5 days per week for eight weeks (i.e., Day -56 to Day 0, 500 mJ / cm2 / dose, a total of 40 doses) to induce senescence in the skin. A visual scheme of the experimental procedure is shown below in FIG.2. Post-UVB irradiation, P1 and P2 (assessed in Example 1) were dosed intradermally to the rats. Peptides were dosed twice per week with a total of 50 µg peptide per dose for 21 days post-UVB irradiation (Day 0 to Day 21). Sites of injection were marked with indelible ink to ensure the continuous treatment of the same area of skin. Rats were sacrificed on Days 0, 7, 14, and 21 and skin samples were harvested for senescence-associated beta-galactosidase (SA-beta-gal) analysis. SA-beta-gal staining is a cytochemical staining method where the X-galchromogen (5-bromo-4-chloro-3- -d-galactopyranoside) is applied directly to thetissues of interest. X-gal is a direct substrate for SA-beta-gal, which cleaves X-gal into galactose and 5-bromo-4-chloro-3-hydroxindole, the later of which shows blue color,allowing for visualization using an inverted or upright light microscope. After detection bymicroscopy, data processing software, such as ImageJ, was used to quantify the percentage of tissue that was SA-beta-gal positive. After staining and microscopy, skin sections were analyzed for percent beta-galactosidase- positive (% beta-gal+) area of the epidermis and dermis using ImageJ software. Values were then plotted using GraphPad Prism software. FIG.3 shows representative SA-beta- gal-stained skin tissues and FIG.4 shows results from ImageJ quantification of % beta-gal+area in the epidermis and dermis. SA-beta-gal is blue, as indicated by dark portions, orspots on the eosin-stained background in the tissues shown in FIG. 3. Table 3 of this ATTORNEY DOCKET: 05336.0005WO01 Example shows the percent reduction of % beta-gal+area in the epidermis and dermis of the active senolytic peptide (P1) compared to the inactive peptide (P2). In all cases, P1 was more effective at reducing the % beta-gal+area than P2, and in some cases, it was as much as 95% more effective. Table 3. Percent Reduction of % beta-gal+area. Time (Days Post-UVB) Tissue 714 21 c aging model in mice Female Balb / c mice (4-weeks old at study initiation) were exposed to a total of 10 Gy of ionizing gamma-irradiation spread over a total of 10 doses over a 4-week period (i.e., Day - 28 to Day 0, 0.5 Gy / dose, 10 total doses) to induce senescence systemically. A visual scheme of the experimental procedure is shown in FIG.5. For Group 1, P1 and P2 (assessed in Examples 1 and 2) were dosed intraperitoneally three times per week at adose level of 5 mg / kg per dose during the gamma-irradiation treatment period (i.e., Day -28to Day 0). For Group 2, P1 and P2 were dosed intraperitoneally three times per week at a dose level of 5 mg / kg per dose after the gamma-irradiation treatment period (i.e., Day 0 to Day 56). Mice were sacrificed on Days 0, 28, and 56 and liver, spleen, and kidney tissues were harvested for both SA-beta-gal analysis and p16 staining. SA-beta-gal staining was performed as described previously. p16 staining was performed on sectioned tissues usingAlexaFluor647 (red) labeled anti-p16 antibody. Anti-p16 antibody was applied directly tosectioned tissues on a glass slide. After an incubation period and various washing steps to reduce non-specific antibody staining, DAPI (4’,6-Diamidino-2-Phenylindole, Dihydrochloride) was applied to the tissues for nuclear visualization. DAPI is a dark bluedye that labels nuclear DNA, allowing for visualization of the nucleus within cells. After asecond incubation period to allow DAPI entry into and staining of nuclear DNA, various washing steps were performed to avoid background staining. After staining with anti-p16 antibody and DAPI, inverted fluorescence microscopy was used to visualize p16+(red) and DAPI+(blue) areas of the tissues. ATTORNEY DOCKET: 05336.0005WO01 After staining and microscopy, organ sections were analyzed for % beta-gal+area and p16mean fluorescence intensity (MFI) using ImageJ software. Values were then plotted usingGraphPad Prism software. There was no significant SA-beta-gal or p16 accumulation seen until Day 56, so only this data point is shown. FIG.6 shows representative SA-beta-gal- stained tissues and FIG.7 shows results from ImageJ quantification of % beta-gal+area in the liver, kidneys, and spleen. SA-beta-gal is blue, as indicated by dark portions, or spots, in the tissues shown in FIG.6. FIG.8, FIG.9 and FIG.10 show representative p16 stained liver, spleen, and kidney, respectively, and FIG.11 shows results from ImageJ quantification of p16 MFI. For FIG.8 to FIG.10, p16 staining is red appearing as lightspots, whereas DAPI staining is blue appearing as darker spots. Table 4 of this Exampleshows the percent reduction of % beta-gal+area in the liver, kidneys, and spleen of the active senolytic peptide (P1) compared to the inactive peptide (P2) for both Group 1 and Group 2 (peptides injected during gamma-irradiation and peptides injected after gamma-irradiation, respectively). In all cases, P1 was more effective at reducing the % beta-gal+area than P2, in some cases, P1 was as much as 74% more effective. Table 5 shows the percent reduction of p16 MFI in the liver, kidneys, and spleen of the active senolytic peptide P1 compared to the inactive peptide P2 for both Group 1 and Group 2 (peptides were injected during gamma-irradiation and peptides were injected after gamma-irradiation, respectively). In all cases, P1 was more effective than P2 at reducing the p16 MFI, and in some cases, P1 was as much as 85% more effective. Table 4. Percent reduction of % beta-gal+area of P1 compared to P2. Tissue Group 1 Group 2 ATTORNEY DOCKET: 05336.0005WO01 Table 5: Percent reduction of p16 MFI of P1 compared to P2. Tissue Group 1 Group 2Liv r 7 2 d in vivo Cell penetrating peptides (CPPs) are assessed to identify those having increased senolytic activity and reduced effects in healthy, proliferating cells. A peptidomimetic approach is taken to optimize P1 assessed in Examples 1-3. To validate new senolytic CPPs, in vitroand in vivo experiments are performed.In vitro experiments involve inducing senescence in IMR-90 fibroblasts using gamma-irradiation and treating senescent, and healthy, proliferating IMR-90 cells as controls, with senolytic CPPs. In brief, on Day 0, IMR-90 fibroblasts are plated in tissue culture (TC)- flasks and adhered overnight. To induce senescence, cells are exposed to 10 grays (Gy) of ionizing -irradiation on Day 1. Cells are kept in culture from Days 2-8, serving as both a recovery period and to allow cells to enter a senescent state. Cellular senescence is confirmed by SA-beta-gal staining. On Day 9, senolytic CPPs and controls are added to senescent IMR-90 fibroblasts and, as a control for senolytic activity, proliferating IMR-90 fibroblasts. Test peptides and control peptides are added to cells starting at 100 µM andsuccessively diluted by half-log dilutions down to 3.16 nM. Cells are then incubated in thepresence of peptides for a total of 5 days. Cells are replenished with fresh media and peptides 3 days after initial addition of peptides (i.e., Day 12 of the assay). On the final dayof the assay, Day 14, cell viability is analyzed using a CellTiterGlo (Promega) luminescentviability assay. Relative cell viability is normalized to the lowest peptide concentration and relative viability values are calculated. Relative viability values are then plotted and EC50 values calculated using GraphPad Prism Software.In vivo experiments involve inducing senescence in mice and rats using establishedaccelerated aging models using UVB irradiation and gamma-irradiation for skin aging in rats and systemic aging in mice, respectively. ATTORNEY DOCKET: 05336.0005WO01UVB Model Skin Aging: Male CD-IGS (Sprague Dawley) rats (4-weeks old at studyinitiation) are exposed to a total of 20,000 mJ / cm2 of UVB irradiation 5 days per week foreight weeks (i.e., Day -56 to Day 0, 500 mJ / cm2 / dose, a total of 40 doses) to induce senescence in the skin. Post-UVB irradiation, test peptides are dosed intradermally to rats. Peptides are dosed once, twice, three times, four times, or five times per week with a totalof 50 micrograms peptide per dose for 21 days post-UVB irradiation (i.e., Day 0 to Day 21).Marking sites of injection with indelible ink ensures continuous treatment of the same area of skin. Rats are sacrificed on Days 0, 7, 14, and 21 and skin samples are harvested for SA-beta-gal and p16 analysis. After staining and microscopy, skin sections are analyzed for % beta-gal+area and p16 MFI of the epidermis and dermis using ImageJ software. Values are plotted using GraphPad Prism software.Gamma-irradiation Systemic Aging Model: Female Balb / c mice (4-weeks old at studyinitiation) are exposed to a total of 10 Gy of ionizing gamma-irradiation spread over a total of 10 doses over a 4-week period (i.e., Day -28 to Day 0, 0.5 Gy / dose, 10 total doses) toinduce senescence systemically. Various dosing regimens are tested including dosingduring gamma-irradiation, after gamma-irradiation, and both during and after gamma-irradiation. Test peptides are dosed intraperitoneally three times per week at a dose levelof 5 mg / kg per dose. Mice are sacrificed on Days 0, 14, 28, and 56 and liver, spleen, and kidney (among other) tissues are harvested for both SA-beta-gal analysis and p16 staining. After staining and microscopy, organ sections are analyzed for % beta-gal+area and p16 MFI using ImageJ software. Values are then plotted using GraphPad Prism software.These studies can identify CPPs having effective senolytic activity indicated by reducedbeta-gal+cells in tissues along with reduced aging-associated lesions in the skin and reduced aging-associated disorders. Example 5: Preparation of particles containing cell penetrating peptide and cargo Nanoparticles having senomorphic and senolytic activity are prepared by electrostaticcondensation of a cell penetrating peptide (CPP) and a JAK inhibitor. CPPs are cationicand are routinely used as delivery vehicles to condense anionic nucleic acid (for example,DNA or mRNA) into nanoparticles, which are then used as biochemical tools ortherapeutics. ATTORNEY DOCKET: 05336.0005WO01 A JAK kinase inhibitor of Formula B has been developed that shows potent inhibition of the production of various cytokines related to senescence and accelerated aging. The compound of Formula B, referred to as C1 herein, forms an anionic salt, and is used to form a senomorphic and senolytic therapeutic nanoparticle with P1 or other cationic CPP. To test optimal nanoparticle formation, various ratios of cationic senolytic CPP and anionic C1 salt are tested. Varying ratios of the two components are mixed and vortexed, allowed to sit at room temperature for one hour for nanoparticle formation, and then dynamic light scattering (DLS) is used to measure mean particle diameter and polydispersity. Optimal mean particle diameters of less than 100 nm allow for optimal cellular transfection and in vivo biodistribution. Preparations of C1 with CPPs are assessed by in vitro and in vivo assays described in Example 4. For both mouse and rat in vivo experiments, tissues are also collected and dissociated for SASP cytokine and chemokine analysis using either ELISA or multiplexing. For in vitro experiments, conditioned media is collected, and SASP-associated cytokines and chemokines are analyzed using ELISA or multiplexing assays. These studies can show that C1 and related analogs can reduce the SASP and can result in reduced aging-associated lesions in the skin. Example 6: Naturally aged mouse model for assessing treatmentFemale, immune competent, C57BL / 6J mice (between 30- and 90-weeks old at studyinitiation) are purchased from a commercial vendor after being housed under normalvivarium conditions to produce a naturally aged mouse model. Test peptides are dosedintraperitoneally, initially three times per week at a dose level of 5 mg / kg per dose. Miceare sacrificed on Days 0, 14, 28, and 56 (post initiation of treatment) and liver, spleen, and kidney (among other) tissues are harvested for both SA-beta-gal analysis and p16 staining, among other potential aging-related biomarkers, such as urokinase plasminogen activator receptor (uPAR) and / or DNA damage histone marker gamma-H2AX. uPAR or gamma-H2AX staining is performed on sectioned tissues using AlexaFluor647 (red)-labeled anti-uPAR or anti-gamma-H2AX antibody. Anti-uPAR or anti-gamma-H2AX antibody is applied directly to sectioned tissues on a glass slide. After an incubation period and various washing steps to reduce non-specific antibody staining, DAPI (4’,6-Diamidino- 2-Phenylindole, Dihydrochloride) is applied to the tissues for nuclear visualization. DAPI is ATTORNEY DOCKET: 05336.0005WO01 a dark blue dye that labels nuclear DNA, allowing for visualization of the cell nucleus. After a second incubation period to allow time for DAPI nuclear staining, various washing steps are performed to avoid background staining. After both staining steps with anti-uPAR or anti-gamma-H2AX antibody and DAPI, inverted fluorescence microscopy is used tovisualize uPAR+ or gamma-H2AX+ (red) and DAPI+ (blue) areas of the tissues. Afterstaining and microscopy, organ sections are analyzed for % beta-gal+ area, and uPARmean fluorescence intensity (MFI) or gamma-H2AX MFI, using ImageJ software. Valuesare then plotted using GraphPad Prism software. Analysis of % beta-gal+ area and MFI aredescribed in Examples 2 and 3. These studies can identify CPPs having effective senolyticactivity indicated by reduced beta-gal+cells in tissues along with reduced aging-associated lesions in the skin and reduced aging-associated disorders.Example 7: Targeted cell-penetrating peptide administrationIn certain instances, a senolytic treatment is desired in the central nervous system. For thatpurpose, a cell-penetrating peptide (CPP) needs to efficiently cross the blood-brain barrier(BBB). The peptide pVEC (derived from murine VE-Cadherin; SEQ ID NO:13) is anexample of one CPP that has been shown to efficiently cross the BBB (Stalmans et al., Plos One: World Wide Web URL address doi.org / 10.1371 / journal.pone.0139652 (2015)). Various doses of pVEC are tested to reverse markers of aging in distinct brain domains,such as the hippocampus and cerebral cortex, displaying significantly increased levels ofsenescent cell-associated beta-gal staining after 60 weeks. Refer to Figure 12 for SA-beta-Gal quantification of various tissues in aged mice.Additionally, the homologous sequence from murine VE-Cadherin, pVEC (SEQ ID NO:13),is tested. Effect of exposure to pVEC and / or homologous hu-pVEC (SEQ ID NO:14) onbeta-gal staining, and optionally one or more additional senescent cell markers, in thehippocampus or cerebral cortex, and other brain regions, such as substantia nigra andbasal ganglia, is assessed. Administration of pVEC or hu-pVEC may result in betterperformance on cognitive ability tests and a prolonged health span.Pertinent to the animal model and studies described in Example 6 and Example 7, FIG.12shows SA-beta-Gal % levels in different tissues of naturally aged mice between six weeksof age and 90 weeks of age that have not been treated with a cell-penetrating peptidecomposition. ATTORNEY DOCKET: 05336.0005WO01 ** *The entirety of each patent, patent application, publication and document referencedherein is incorporated by reference. Citation of patents, patent applications, publicationsand documents is not an admission that any of the foregoing is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents.Their citation is not an indication of a search for relevant disclosures. All statementsregarding the date(s) or contents of the documents is based on available information and is not an admission as to their accuracy or correctness.The technology has been described with reference to specific implementations. The termsand expressions that have been utilized herein to describe the technology are descriptive and not necessarily limiting. Certain modifications made to the disclosed implementationscan be considered within the scope of the technology. Certain aspects of the disclosedimplementations suitably may be practiced in the presence or absence of certain elementsnot specifically disclosed herein.Each of the terms “comprising,” “consisting essentially of,” and “consisting of” may bereplaced with either of the other two terms. The term “a” or “an” can refer to one of or aplurality of the elements it modifies (e.g., “a reagent” can mean one or more reagents) unless it is contextually clear either one of the elements or more than one of the elementsis described. The term “about” as used herein refers to a value within 10% of theunderlying parameter (i.e., plus or minus 10%; e.g., a weight of “about 100 grams” caninclude a weight between 90 grams and 110 grams). Use of the term “about” at thebeginning of a listing of values modifies each of the values (e.g., “about 1, 2 and 3” refersto "about 1, about 2 and about 3"). When a listing of values is described, the listingincludes all intermediate values and all fractional values thereof (e.g., the listing of values "80%, 85% or 90%" includes the intermediate value 86% and the fractional value 86.4%). When a listing of values is followed by the term "or more," the term "or more" applies to each of the values listed (e.g., the listing of "80%, 90%, 95%, or more" or "80%, 90%, 95%or more" or "80%, 90%, or 95% or more" refers to "80% or more, 90% or more, or 95% ormore"). When a listing of values is described, the listing includes all ranges between any two of the values listed (e.g., the listing of "80%, 90% or 95%" includes ranges of "80% to 90%," "80% to 95%" and "90% to 95%").Certain implementations of the technology are set forth in the claim(s) that follow(s).

Claims

ATTORNEY DOCKET: 05336.0005WO01 What is claimed is:

1. A method for reducing a senescent cell population, comprising administering acomposition comprising an active ingredient to cells in an amount sufficient to reducethe senescent cell population, wherein the active ingredient consists essentially of a cell penetrating peptide.

Images