WO2024039646A1 - Procédés et matériaux pour utiliser et évaluer des traitements anti-sénescence chez des mammifères - Google Patents

Procédés et matériaux pour utiliser et évaluer des traitements anti-sénescence chez des mammifères Download PDF

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WO2024039646A1
WO2024039646A1 PCT/US2023/030229 US2023030229W WO2024039646A1 WO 2024039646 A1 WO2024039646 A1 WO 2024039646A1 US 2023030229 W US2023030229 W US 2023030229W WO 2024039646 A1 WO2024039646 A1 WO 2024039646A1
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mammal
papp
senotherapeutic
treatment
agents
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PCT/US2023/030229
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Jair Machado ESPINDOLA NETTO
James L. Kirkland
Yi Zhu
Tamar TCHKONIA
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Mayo Foundation For Medical Education And Research
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5082—Supracellular entities, e.g. tissue, organisms
    • G01N33/5088—Supracellular entities, e.g. tissue, organisms of vertebrates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
    • A61K2800/782—Enzyme inhibitors; Enzyme antagonists
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
    • G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
    • G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
    • G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
    • G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
    • G01N2333/96486—Metalloendopeptidases (3.4.24)
    • G01N2333/96491—Metalloendopeptidases (3.4.24) with definite EC number
    • G01N2333/96494—Matrix metalloproteases, e. g. 3.4.24.7
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • This document relates to methods and materials for assessing and/or using antisenescence treatments (e.g., admini strati on(s) of one or more senotherapeutic agents) within a mammal (e.g., a human).
  • antisenescence treatments e.g., admini strati on(s) of one or more senotherapeutic agents
  • the methods and materials provided herein can be used to determine and/or classify the efficacy of an anti-senescence treatment in a mammal (e.g., a human).
  • the level of pregnancy-associated plasma protein-A (PAPP-A) polypeptides in a sample obtained from a mammal (e.g., a human) having been administered an anti-senescence treatment (e.g., admini stration(s) of one or more senotherapeutic agents) can be used to determine and/or classify the efficacy of the anti-senescence treatment in treating the mammal.
  • an anti-senescence treatment e.g., admini stration(s) of one or more senotherapeutic agents
  • PAPP-A is a secreted zinc metalloprotease.
  • the major function of PAPP-A polypeptides is to enhance insulin-like growth factor (IGF) signalling through their ability to degrade inhibitory IGF binding proteins (IGFBPs) such as IGFBP2, IGFBP-5, and IGFBP-4.
  • IGFBPs inhibitory IGF binding proteins
  • PAPP-A polypeptides can modulate IGF bioavailability in the paracrine and autocrine pathways independently of systemic levels of IGF 1.
  • the PAPP-A-IGF pathway plays a role in cell growth, differentiation, and transformation.
  • This document provides methods and materials for assessing the efficacy of and/or using an anti-senescence treatment (e.g., admini stration(s) of one or more senotherapeutic agents).
  • the methods and materials provided herein can be used to determine the efficacy of an anti-senescence treatment in a mammal (e.g., a human).
  • a mammal e.g., a human
  • the level of PAPP-A polypeptides in a sample e.g., a blood sample, a urine sample, or a saliva sample
  • a mammal e.g., a human
  • this document provides methods and materials for treating a mammal (e.g., a human) having a disease or disorder characterized by the presence of senescent cells or an elevated number of senescent cells.
  • a mammal e.g., a human
  • an antisenescence treatment e.g., one or more senotherapeutic agents
  • a reduced level of PAPP- A polypeptides within the mammal can indicate that the administered anti-senescence treatment effectively reduced the number of senescent cells within that mammal, while a lack of a reduced level of PAPP-A polypeptides within the mammal can indicate that the administered anti-senescence treatment did not effectively reduce the number of senescent cells within that mammal.
  • senescent cells can secrete PAPP-A polypeptides and/or can promote the expression of PAPP -A polypeptides from other cells.
  • treating a mammal with an anti-senescence treatment e.g., administering one or more senotherapeutic agents to a mammal
  • that particular anti-senescence treatment can be continued within that mammal.
  • the mammal can be treated with an alternative anti-senescence treatment.
  • the same agents can be administered to the mammal but at an increased dosing level (e.g., higher amount of agent(s) or more frequent administration of the same amount of agent(s)) or a different agent or set of agents can be administered to the mammal.
  • the level of PAPP- A polypeptides within a mammal can be monitored during an anti-senescence treatment to assess effectiveness of the anti-senescence treatment and/or to make adjustments to an anti-senescence treatment when it is determined to be not effective.
  • one aspect of this document features methods for assessing efficacy of an anti-senescence treatment.
  • the methods can include, consist of, or consist essentially of, (a) determining whether or not a mammal has a reduced level of PAPP- A polypeptides following administration of one or more senotherapeutic agents to the mammal as compared to the level of PAPP-A polypeptides within the mammal prior to the administration of the one or more senotherapeutic agents; (b) classifying the anti-senescence treatment as being effective in the mammal if the mammal has the reduced level; and (c) classifying the anti-senescence treatment as not being effective in the mammal if the mammal does not have the reduced level.
  • the mammal can be a human.
  • the determining step can include comparing the level of PAPP-A polypeptides within a first sample obtained from the mammal prior to the administration of the one or more senotherapeutic agents to the level of PAPP- A polypeptides within a second sample obtained from the mammal after the administration of the one or more senotherapeutic agents.
  • the first and second samples can be blood samples.
  • the first and second samples can be urine samples.
  • the first and second samples can be saliva samples.
  • the one or more senotherapeutic agents can be dasatinib, quercetin, navitoclax, Al 331852, Al 155463, fisetin, luteolin, geldanamycin, tanespimycin, alvespimycin, piperlongumine, panobinostat, FOXO4-related peptides, nutlin-3a, ruxolitinib, metformin, or rapamycin.
  • the method can include determining that the mammal has the reduced level and classifying the anti-senescence treatment as being effective in the mammal.
  • the method can include administering the anti-senescence treatment to the mammal after the determining step.
  • the method can include determining that the mammal does not have the reduced level and classifying the anti-senescence treatment as not being effective in the mammal.
  • the method can include administering a revised anti-senescence treatment that can be different from the anti-senescence treatment administered to the mammal after the determining step.
  • the revised anti-senescence treatment can include administering a higher amount of the one or more senotherapeutic agents of the anti- senescence treatment.
  • the revised anti-senescence treatment can include administering one or more senotherapeutic agents different from the one or more senotherapeutic agents of the anti- senescence treatment.
  • the method can include administering the anti-senescence treatment to the mammal prior to the determining step.
  • this document features methods for treating a mammal.
  • the methods can include, consist of, or consist essentially of, (a) determining whether or not a mammal has a reduced level of PAPP- A polypeptides following a previous administration of one or more senotherapeutic agents to the mammal as compared to the level of PAPP -A polypeptides within the mammal prior to the previous administration; (b) administering the one or more senotherapeutic agents to the mammal if the mammal has the reduced level; and (c) administering, to the mammal, (i) a higher amount of the one or more senotherapeutic agents of the previous administration or (ii) one or more senotherapeutic agents that are different from the one or more senotherapeutic agents of the previous administration, if the mammal does not have the reduced level.
  • the mammal can be a human.
  • the determining step can include comparing the level of PAPP-A polypeptides within a first sample obtained from the mammal prior to the previous administration to the level of PAPP-A polypeptides within a second sample obtained from the mammal after the previous administration.
  • the first and second samples can be blood samples.
  • the first and second samples can be urine samples.
  • the first and second samples can be saliva samples.
  • the one or more senotherapeutic agents can be dasatinib, quercetin, navitoclax, A1331852, Al 155463, fisetin, luteolin, geldanamycin, tanespimycin, alvespimycin, piperlongumine, panobinostat, F0X04- related peptides, nutlin-3 a, ruxolitinib, metformin, or rapamycin.
  • the method can include determining that the mammal has the reduced level.
  • the administering the one or more senotherapeutic agents to the mammal of step (b) can include administering the one or more senotherapeutic agents to the mammal in the same manner as the previous administration.
  • the method can include determining that the mammal does not have the reduced level.
  • the administering of step (c) can include administering the higher amount of the one or more senotherapeutic agents of the previous administration to the mammal.
  • the administering of step (c) can include administering the one or more senotherapeutic agents that are different from the one or more senotherapeutic agents of the previous administration.
  • this document features methods for continuing a previous antisenescence treatment.
  • the methods can include, consist of, or consist essentially of, administering an anti-senescence treatment that can be the same as a previous antisenescence treatment to a mammal identified as having a reduced level of PAPP- A polypeptides following the previous administration as compared to the level of PAPP -A polypeptides within the mammal prior to the previous administration.
  • the mammal can be a human.
  • the mammal can be identified as having the reduced level by comparing the level of PAPP-A polypeptides within a first sample obtained from the mammal prior to the previous anti- senescence treatment to the level of PAPP-A polypeptides within a second sample obtained from the mammal after the previous anti-senescence treatment.
  • the first and second samples can be blood samples.
  • the first and second samples can be urine samples.
  • the first and second samples can be saliva samples.
  • the one or more senotherapeutic agents can be dasatinib, quercetin, navitoclax, A1331852, Al 155463, fisetin, luteolin, geldanamycin, tanespimycin, alvespimycin, piperlongumine, panobinostat, FOXO4-related peptides, nutlin- 3a, ruxolitinib, metformin, or rapamycin.
  • this document features methods for changing an ineffective use of a previous anti-senescence treatment.
  • the methods can include, consist of, or consist essentially of, administering an anti-senescence treatment that can be different from a previous anti-senescence treatment to a mammal identified as not having a reduced level of PAPP-A polypeptides following the previous administration as compared to the level of PAPP-A polypeptides within the mammal prior to the previous administration.
  • the mammal can be a human.
  • the mammal can be identified as not having the reduced level by comparing the level of PAPP-A polypeptides within a first sample obtained from the mammal prior to the previous anti-senescence treatment to the level of PAPP-A polypeptides within a second sample obtained from the mammal after the previous anti-senescence treatment.
  • the first and second samples can be blood samples.
  • the first and second samples can be urine samples.
  • the first and second samples can be saliva samples.
  • the one or more senotherapeutic agents can be dasatinib, quercetin, navitoclax, A1331852, Al 155463, fisetin, luteolin, geldanamycin, tanespimycin, alvespimycin, piperlongumine, panobinostat, FOX04-related peptides, nutlin-3a, ruxolitinib, metformin, or rapamycin.
  • this document features methods for reducing the level of a PAPP -A polypeptide within a mammal.
  • the methods can include, consist of, or consist essentially of, administering one or more senotherapeutic agents to a mammal.
  • the mammal can be a human.
  • the mammal can be identified as being in need of a reduced level of PAPP-A polypeptides.
  • the one or more senotherapeutic agents can be dasatinib, quercetin, navitoclax, A1331852, Al 155463, fisetin, luteolin, geldanamycin, tanespimycin, alvespimycin, piperlongumine, panobinostat, FOXO4-related peptides, nutlin-3a, ruxolitinib, metformin, or rapamycin.
  • the method can include determining, after the administering step, that the level of PAPP-A polypeptides was reduced within the mammal following the administering step.
  • the determining step can include comparing the level of PAPP-A polypeptides within a first sample obtained from the mammal prior to the administering step to the level of PAPP-A polypeptides within a second sample obtained from the mammal after the administering step.
  • the first and second samples can be blood samples.
  • the first and second samples can be urine samples.
  • the first and second samples can be saliva samples.
  • this document features senotherapeutic agents for use in the preparation of a medicament to reduce the level of PAPP-A polypeptides within a mammal.
  • the mammal can be a human
  • this document features senotherapeutic agents for use in reducing the level of PAPP-A polypeptides within a mammal.
  • the mammal can be a human.
  • Figures 1 A - IB show that PAPP-A polypeptide expression and IGF-1 polypeptide expression were increased in senescent human adipose-derived progenitors (preadipocytes; Figure 1A) and in senescent human umbilical vein endothelial cells (HUVECs; Figure IB) relative to non-senescent cells.
  • preadipocytes Figure 1A
  • HAVECs senescent human umbilical vein endothelial cells
  • the amount of PAPP-A and IGF-1 RNA was assessed by relative RT-PCR in non-senescent cells and in cells made senescent by ionizing radiation.
  • Figures 2A - 2B show that senolytic drugs reduced secretion of PAPP-A polypeptides from human adipose tissue.
  • Figure 2A is a graph of a level of PAPP-A polypeptides measured by ELISA and normalized to total protein in CM. Data are expressed as a ratio to vehicle-treated tissue.
  • Statistical analysis used a one-way ANOVA, P ⁇ 0.009 and Tukey multiple comparisons *P ⁇ 0.048, **P ⁇ 0.008.
  • Tissue was digested, and PAPP-A mRNA was measured by relative RT-PCR.
  • a TATA box binding protein (TBP) was used as a control.
  • PAPP-A polypeptide expression was standardized to the PAPP-A level in vehicle-treated tissue. *P ⁇ 0.0018.
  • Figure 3 shows paracrine effects of senolytic drugs on regulators of PAPP-A polypeptide expression in human adipose tissue.
  • mRNA expression of pl 6, TL-la, TL-i p, and TL6 polypeptides was measured by relative RT-PCR. Fold change of mRNA expression in senolytic-treated cells was standardized to PAPP-A expression in the vehicle-treated cells and are shown in the heat map.
  • This document provides methods and materials for assessing anti-senescence treatments as well as methods and materials for effectively using anti-senescence treatments within mammals. For example, this document provides methods and materials for determining whether or not a particular anti-senescence treatment administered to a mammal (e g., a human) is effective (e g., is effective to reduce the number of senescent cells within that mammal).
  • a mammal e g., a human
  • determining that a mammal e.g., a human
  • determining that a mammal e.g., a human
  • Any appropriate mammal can be administered an anti-senescence treatment and have its effectiveness assessed as described herein. Any appropriate mammal that was administered or instructed to self-administer an anti-senescence treatment can be assessed as described herein to determine if the anti-senescence treatment is effective in that mammal. Any appropriate mammal can be treated with one or more anti-senescence treatments that can be assessed as described herein to arrive at a particular anti-senescence treatment that is determined to be effective in that mammal. Examples of mammals that can be assessed and/or treated as described herein include, without limitation, humans, non-human primates such as monkeys, dogs, cats, horses, cows, pigs, sheep, mice, and rats.
  • the mammal can be any appropriate age.
  • the human when assessing and/or treating a human as described herein, can be an adult that is at least 18 years of age (e.g., about 19, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90 years of age).
  • a mammal e.g., a human having been administered an anti-senescence treatment (e.g., having been administered one or more senotherapeutic agents) can be assessed to determine and/or classify the efficacy of the anti-senescence treatment.
  • an anti-senescence treatment e.g., having been administered one or more senotherapeutic agents
  • a mammal e.g., a human having been administered an anti-senescence treatment (e.g., having been administered one or more senotherapeutic agents) can be assessed to determine whether or not the anti-senescence treatment is effective within that mammal by comparing the level of PAPP-A polypeptides in a sample (e.g., a blood sample, a urine sample, or a saliva sample) obtained from the mammal following the anti- senescence treatment to the level of PAPP-A polypeptides in a comparable sample obtained from the mammal prior to the anti-senescence treatment.
  • a sample e.g., a blood sample, a urine sample, or a saliva sample
  • senescent cells within a mammal can secrete PAPP-A polypeptides that can be detected in that mammal’s bodily fluids (e.g., in that mammal’s blood, urine, and/or saliva) and/or tissues (e.g., adipose tissues).
  • bodily fluids e.g., in that mammal’s blood, urine, and/or saliva
  • tissues e.g., adipose tissues
  • levels of PAPP-A polypeptides can be used to determine whether the number of senescent cells in a mammal (e.g., a human) are increasing, decreasing, or staying the same or essentially the same, and can therefore be used to determine and/or classify whether or not an anti-senescence treatment is effective (e.g., whether or not an anti-senescence treatment reduced the number of senescent cells within the mammal).
  • an anti- senescence treatment is determined to be effective, the same antisenescence treatment can be administered to the mammal (e.g., human). In some cases, if an anti-senescence treatment is determined to be effective, an anti-senescence treatment that is a slight modification of the original anti-senescence treatment can be administered to the mammal (e.g., human).
  • an anti-senescence treatment when determined to be effective within a mammal, that mammal can be administered or instructed to self-administer a slightly higher dose (e.g., l.lx or 1.2x that of the original dose) or a slightly lower dose (e g., 0.9x or 0.8x that of the original dose) of the same agents of the effective antisenescence treatment.
  • a slightly higher dose e.g., l.lx or 1.2x that of the original dose
  • a slightly lower dose e.g., 0.9x or 0.8x that of the original dose
  • a revised anti-senescence treatment can be administered.
  • that mammal can be administered or instructed to self-administer a revised anti-senescence treatment that includes (a) an anti-senescence treatment that is different from the previously administered antisenescence treatment(s), (b) an anti- senescence treatment that is of a higher amount of the previously administered one or more senotherapeutic agents of the anti-senescence treatment, and/or (c) an anti-senescence treatment that includes one or more senotherapeutic agents that are different from the one or more senotherapeutic agents of previously administered antisenescence treatment. Any of the methods described herein used to determine if an anti- senescence treatment is effective also can be used to determine if a revised anti- senescence treatment is effective.
  • an anti-senescence treatment that is different from the previously administered anti-senescence treatment can include administering one or more different senotherapeutic agents. Different anti-senescence treatments also can include administering the previously administered one or more senotherapeutic agents and an additional one or more senotherapeutic agent that was not previously administered. In some cases, an antisenescence treatment that is of a higher amount of the previously administered one or more senotherapeutic agents of the anti-senescence treatment can include an increased dosage, a more frequent dosage regime, or both. Increased dosage can include increasing the dosage by, for example, 1.3x, 1.4x, 1.5x, 1.75x, 2x, or more compared to the previous dosage of the administered senotherapeutic agent(s).
  • More frequent dosage regimes can include administering the anti-senescence treatment more frequently (e.g., once a week, once every two weeks, once a month, every 2 months, every 3 months, every 4 months, every 5 months, or every six months) as compared to the previous regime of the administered senotherapeutic agent(s).
  • a sample e.g., a blood sample, a urine sample, or a saliva sample
  • a mammal e.g., a human
  • an anti-senescence treatment e.g., having been administered one or more senotherapeutic agents
  • the level of PAPP- A polypeptides in the sample obtained from a mammal after the mammal was administered an anti-senescence treatment can be compared to the level of PAPP -A polypeptides within a comparable sample obtained from the mammal prior to the mammal being administered the anti-senescence treatment.
  • the level of PAPP-A polypeptides in the sample obtained from a mammal after the mammal was administered an anti-senescence treatment can be compared to a cutoff level of PAPP- A polypeptides that can be used to identify reduced levels of PAPP-A polypeptides that are indicative of an effective anti-senescence treatment in that mammal.
  • a cutoff level of PAPP-A polypeptides that can be used to identify reduced levels of PAPP- A polypeptides that are indicative of an effective anti-senescence treatment in that mammal can be about 30 nanogram (ng) per milliliter (mL) (e.g., from about 19 ng per mL to about 40 ng per mL, from about 19 ng per mL to about 35 ng per mL, from about 19 ng per mL to about 30 ng per mL, from about 19 ng per mL to about 25 ng per mL, from about 25 ng per mL to about 40 ng per mL, from about 30 ng per mL to about 40 ng per mL, from about 35 ng per mL to about 40 ng per mL, from about 20 ng per mL to about 35 ng per mL, from about 23 ng per mL to about 32 ng per mL, from about 20 ng per mL to
  • a cutoff level of PAPP-A polypeptides that can be used to identify reduced levels of PAPP- A polypeptides that are indicative of an effective anti- senescence treatment in a male human can be about 23 ng per mL (e.g., can be from about 19 ng per mL to about 24 ng per mL, from about 19 ng per mL to about 22 ng per mL, from about 19 ng per mL to about 20 ng per mL, from about 20 ng per mL to about 22 ng per mL, from about 19 ng per mL to about 21 ng per mL, or from about 20 ng per mL to about 22 ng per mL) of whole blood.
  • a cutoff level of PAPP-A polypeptides that can be used to identify reduced levels of PAPP- A polypeptides that are indicative of an effective anti- senescence treatment in a female human can be about 34 ng per mL (e.g., can be from about 25 ng per mL to about 37 ng per mL, from about 25 ng per mL to about 35 ng per mL, from about 25 ng per mL to about 30 ng per mL, from about 25 ng per mL to about 28 ng per mL, from about 28 ng per mL to about 37 ng per mL, from about 30 ng per mL to about 37 ng per mL, from about 33 ng per mL to about 37 ng per mL, from about 28 ng per mL to about 35 ng per mL, from about 30 ng per mL to about 33 ng per mL, from about 27 ng per mL to about 30 ng
  • a cutoff level of PAPP-A polypeptides that can be used to identify reduced levels of PAPP-A polypeptides that are indicative of an effective anti-senescence treatment in a mammal can be as described elsewhere (e.g., Coskun et al., (2013) Journal of Cardiology. 61: 128-131, at, for example, the abstract).
  • a sample (e.g., a blood sample, a urine sample, or a saliva sample) can be obtained from a mammal (e.g., a human) before and/or after the mammal has been administered an anti-senescence treatment (e.g., one or more senotherapeutic agents).
  • an anti-senescence treatment e.g., one or more senotherapeutic agents.
  • a sample e.g., a blood sample, a urine sample, or a saliva sample
  • a mammal e.g., a human
  • a sample e.g., a blood sample, a urine sample, or a saliva sample
  • a mammal e.g., a human
  • a mammal e.g., a human
  • Such a determined level of PAPP-A polypeptides within the mammal prior to being administered the anti- senescence treatment can be used to determine if the level of PAPP- A polypeptides within the mammal determined after the mammal has been administered an anti-senescence treatment is reduced, is elevated, or remains the same following the anti-senescence treatment.
  • a reduction in the level of PAPP- A polypeptides within the mammal after the mammal has been administered an antisenescence treatment can indicate that an anti-senescence treatment is effective in that mammal.
  • a sample e.g., a blood sample, a urine sample, or a saliva sample
  • mammal e.g., a human
  • a sample can be obtained from mammal (e.g., a human) during the time that the mammal is administered an anti-senescence treatment and assessed to determine the level of PAPP-A polypeptides within the mammal at that time.
  • a sample e g., a blood sample, a urine sample, or a saliva sample
  • a mammal e.g., a human
  • the same time e.g., at the start of an anti-senescence treatment
  • the mammal is being administered an antisenescence treatment and assessed to determine the level of PAPP -A polypeptides within the mammal at that time.
  • Such a determined level of PAPP- A polypeptides within the mammal at the time of administration of the anti-senescence treatment can be used to determine if the level of PAPP- A polypeptides within the mammal determined after the mammal has been exposed to the administered anti-senescence treatment for a period of time is reduced, is elevated, or remains the same following the anti-senescence treatment.
  • a reduction in the level of PAPP- A polypeptides within the mammal after the mammal has been exposed to the administered anti-senescence treatment for a period of time can indicate that that an antisenescence treatment is effective in that mammal.
  • a sample e.g., a blood sample, a urine sample, or a saliva sample
  • a sample can be obtained from the mammal (e.g., a human) at any appropriate time after the mammal has been administered an anti-senescence treatment and assessed to determine the level of PAPP-A polypeptides within the mammal after being administered the anti-senescence treatment.
  • a sample e.g., a blood sample, a urine sample, or a saliva sample
  • a mammal e.g., a human
  • a mammal e.g., a human
  • between about 2 weeks and about 6 months e.g., between about 2 weeks and about 5 months, between about 2 weeks and about 4 months, between about 2 weeks and about 3 months, between about 2 weeks and about 2 months, between about 2 weeks and about 1 month, between about 2 weeks and about 3 weeks, between about 3 weeks and about 6 months, between about 1 month and about 6 months, between about 2 months and about 6 months, between about 3 months and about 6 months, between about 4 months and about 6 months, between about 5 months and about 6 months, between about 3 weeks and about 5 months, between about 1 month and about 4 months, or between about 2 months and about 3 months) after an initial administration of an anti-senescence treatment and assessed to determine the level of PAPP-A polypeptides within the mammal after being administered the anti-senescence treatment.
  • Such a determined level of PAPP-A polypeptides within the mammal after being administered the anti-senescence treatment can be used to determine if the level of PAPP- A polypeptides within the mammal determined after the mammal has been administered an anti-senescence treatment is reduced, is elevated, or remains the same following the anti-senescence treatment.
  • a reduction in the level of PAPP- A polypeptides within the mammal after the mammal has been administered an antisenescence treatment can indicate that that an anti- senescence treatment is effective in that mammal.
  • the level of PAPP-A polypeptides within a mammal can be detected at different time points over a course of an anti-senescence treatment (and/or a revised anti- senescence treatment) to determine the efficacy of the anti-senescence treatment (and/or revised anti-senescence treatment).
  • two or more samples e.g., two, three, four, five, six, or more
  • samples e.g., blood samples, urine samples, or saliva samples
  • the level of PAPP-A polypeptides in the samples can be used to determine the efficacy of the anti-senescence treatment (and/or a revised anti-senescence treatment).
  • a first sample e.g., a first blood sample, a first urine sample, or a first saliva sample
  • a mammal e.g., a human
  • an anti-senescence treatment e.g., prior to being administered one or more senotherapeutic agents
  • a second sample e.g., a second blood sample, a second urine sample, or a second saliva sample
  • optionally subsequent samples can be obtained from the mammal after the mammal has been administered the anti-senescence treatment.
  • the anti-senescence treatment e.g., one or more senotherapeutic agents
  • the anti-senescence treatment can be determined and/or classified as being an effective anti-senescence treatment for that mammal.
  • the anti-senescence treatment e g., one or more senotherapeutic agents
  • the anti-senescence treatment can be determined and/or classified as not being an effective treatment for that mammal.
  • a sample can be a biological sample.
  • a sample can contain one or more biological molecules (e.g., nucleic acids such as DNA and RNA, polypeptides, carbohydrates, lipids, hormones, and/or metabolites).
  • samples that can be assessed to determine the level of PAPP-A polypeptides as described herein include, without limitation, fluid samples (e.g., urine samples, saliva samples, and blood samples such as whole blood samples, serum samples, and plasma samples), and tissue samples (e.g., adipose tissue, skin, muscle, heart, vessels, kidney, blood cells, extracellular vesicle tissue, and liver tissue).
  • a biological sample can be a fresh sample or a fixed sample (e.g., a formaldehyde-fixed sample or a formalin-fixed sample).
  • a biological sample can be a processed sample (e.g., to isolate or extract one or more biological molecules).
  • a blood sample can be obtained from a mammal (e.g., a human) and processed to obtain a cellular sample or a polypeptide sample, which can be assessed for the presence, absence, or level of PAPP- A polypeptides as described herein.
  • a mammal e.g., a human
  • a polypeptide sample which can be assessed for the presence, absence, or level of PAPP- A polypeptides as described herein.
  • PAPP- A polypeptides that can be used as described herein include, without limitation, a human PAPP-A polypeptide having the amino acid sequence set forth in National Center for Biotechnology Information (NCBI) GenBank® or GenPept® Accession No.
  • NP_002572.2 a monkey PAPP- A polypeptide having the amino acid sequence set forth in NCBI GenBank® or GenPept® Accession No. XP_014972456.2, a horse PAPP-A polypeptide having the amino acid sequence set forth in NCBI GenBank® or GenPept® Accession No. XP_023484521, a dog PAPP-A polypeptide having the amino acid sequence set forth in NCBI GenBank® or GenPept® Accession No. XP_038347014.1, a cat PAPP-A polypeptide having the amino acid sequence set forth in NCBI GenBank® or GenPept® Accession No.
  • XP_003993206.1 a mouse PAPP-A polypeptide having the amino acid sequence set forth in NCBI GenBank® or GenPept® Accession No. NP_067337.1 , or a rat PAPP-A polypeptide having the amino acid sequence set forth in NCBI GenBank® or GenPept® Accession No. XP_006238331.
  • any appropriate method can be used to detect the presence, absence, or level of PAPP-A polypeptides within a sample (e.g., a sample obtained from a mammal such as a human) to determine the efficacy of an anti-senescence treatment.
  • a sample e.g., a sample obtained from a mammal such as a human
  • the presence, absence, or level of PAPP-A polypeptides within a sample can be determined by detecting the presence, absence, or level of PAPP- A polypeptides in the sample.
  • immunoassays e.g., immunohistochemistry (IHC) techniques and western blotting techniques
  • mass spectrometry techniques e.g., proteomics-based mass spectrometry assays or targeted quantification-based mass spectrometry assays
  • CyTOF time of flight
  • RT-PCR RT-PCR
  • ELISA cytometry by time of flight
  • RT-PCR RT-PCR
  • ELISA ELISA
  • antibodies that can be used in an immunoassay to determine the presence, absence, or level of PAPP- A polypeptides in a sample include, without limitation, PAPP-A/Pappalysin- 1 monoclonal antibodies (e.g., NeoBiotechnologies, PAPPA, 2715, Cat. No. 5069-MSM1-P1), human pappalysin-l/PAPP- A antibodies (e.g., R&D Systems, Cat. No. AF2487), and PAPP-A(pico) ELISA kit antibodies (e.g., ANSH LABs, Cat. No. AL-101).
  • PAPP-A/Pappalysin- 1 monoclonal antibodies e.g., NeoBiotechnologies, PAPPA, 2715, Cat. No. 5069-MSM1-P1
  • human pappalysin-l/PAPP- A antibodies e.g., R&D Systems, Cat. No. AF2487
  • the level of mRNA encoding a PAPP-A polypeptide can be measured to indicate the level of PAPP- A polypeptides within a mammal.
  • a sample containing cells can be obtained from a mammal, and the level of mRNA encoding PAPP-A polypeptides can be measured to determine if the level of PAPP- A polypeptides within the mammal was reduced following administration of an anti-senescence treatment. Any appropriate method can be used to measure the level of mRNA encoding a PAPP-A polypeptide within a sample.
  • PCR polymerase chain reaction
  • RT quantitative reverse transcription
  • qRT-PCR quantitative reverse transcription
  • single cell RNA sequencing single cell RNA sequencing
  • bulk RNA sequencing can be used to determine the presence, absence, or level of mRNA encoding a PAPP-A polypeptide in the sample.
  • the presence, absence, or level of mRNA encoding a PAPP-A polypeptide within a sample can be determined by qRT-PCR.
  • Tn some cases, the presence, absence, or level of mRNA encoding a PAPP-A polypeptide within a sample can be determined as described in Example 2 and/or Example 3.
  • any appropriate anti-senescence treatment can be administered to a mammal (e.g., a human) and be assessed for effectiveness as described herein (e.g., by assessing the level of PAPP-A polypeptides after the mammal has be administered the anti-senescence treatment being assessed).
  • An anti-senescence treatment is a treatment designed to inhibit or reduce cellular senescence within a mammal.
  • an anti-senescence treatment that can be administered to a mammal (e.g., a human) and/or assessed as described herein can be a treatment that includes administering one or more senotherapeutic agents to the mammal (e.g., the human).
  • senotherapeutic agents that can be used as at least a part of an anti- senescence treatment described herein include, without limitation, geroprotector agents such as melatonin, carnosine, metformin, rapamycin, nicotinamide mononucleotide (NMN) and delta sleep-inducing peptide, SASP (senescence-associated secretory phenotype) inhibitors such as glucocorticoids, statins (e.g., simvastatin), JAK1/2 inhibitors (e.g., ruxolitinib), NF-KB inhibitors, p38 inhibitors, and IL- la inhibitors, senolytic agents such as FOXO4-related peptides, BCL-2 inhibitors, Src inhibitors, USP7 inhibitors, quercetin plus dasatinib, fisetin, navitoclax, piperlongumine, azithromycin, roxithromycin, senescence-specific
  • senotherapeutic agents that can be administered and/or assessed as described herein include, without limitation, A1331852, A1155463, luteolin, geldanamycin, tanespimycin, alvespimycin, panobinostat, nutlin-3a, and ruxolitinib.
  • a senotherapeutic agent that can be used as described herein can be a senotherapeutic agent as described elsewhere (see, e.g., Kirkland et al., J. Intern. Med., 288(5):518-536 (2020) at, for example, Table 1).
  • a mammal e.g., a human
  • a mammal e.g., a human
  • the anti-senescence treatment (and/or revised anti-senescence treatment) determined to be effective within that mammal can be continued as is (or with one or more slight alterations).
  • a method for treating a mammal can include administering a previously administered anti-senescence treatment (or slight modification thereof) to a mammal that received that previous anti-senescence treatment and that previous anti-senescence treatment was determined to be effective within that mammal as described herein.
  • that previously effective anti-senescence treatment can be continued as is.
  • that previously effective anti-senescence treatment can be continued with one or more slight alterations.
  • a method for treating a mammal can include administering a first anti-senescence treatment to the mammal, determining that that first anti-senescence treatment is not effective within that mammal as described herein, and administering a second (e.g., a revised anti-senescence treatment) to the mammal (and optionally confirming the effectiveness of that revised anti-senescence treatment within that mammal) as described herein.
  • a mammal e.g., a human
  • a second e.g., a revised anti-senescence treatment
  • a method for treating a mammal can include administering an anti-senescence treatment (e.g., a revised anti-senescence treatment) to a mammal that received a previous anti-senescence treatment that was determined to be ineffective as described herein.
  • an anti-senescence treatment e.g., a revised anti-senescence treatment
  • the administered an anti-senescence treatment can be different from that of the previous antisenescence treatment that was determined to be ineffective.
  • the effectiveness of that administer anti-senescence treatment can be assessed as described herein.
  • a method of treating a mammal (e.g., a human) to inhibit or reduce cellular senescence can include a step of determining whether or not the mammal has a reduced level of PAPP- A polypeptides following a previous administration of an antisenescence treatment to the mammal as compared to the level of PAPP -A polypeptides within the mammal prior to the previous administration.
  • the method can include administering the same anti-senescence treatment (or a slightly modified version thereof) to the mammal (e.g., human) if the mammal has a reduced level of a PAPP-A polypeptide as compared to the level of PAPP-A polypeptides within the mammal prior to the previous administration of an anti-senescence treatment.
  • the method can include administering a revised anti-senescence treatment to the mammal (e.g., human) if the mammal does not have a reduced level of a PAPP-A polypeptide as compared to the level of PAPP-A polypeptides within the mammal prior to the previous administration of an antisenescence treatment.
  • the revised anti-senescence treatment can be a higher dosage amount (e.g., about 1.3x to about 4x higher than the previous administration, about 1 ,4x to about 4x, about 1 ,5x to about 4x, about 1.75x to about 4x, about 2x to about 4x, about 2.5x to about 4x, about 3x to about 4x, about 1 ,3x to about 3x, about 1 ,3x to about 2.5x, about 1.3x to about 2x, about 1.3x to about 1.75x, about 1.3x to about 1.5x, about 1.3x to about 1.4x, about 1.3x, about 1 4x, about 1.5x, about 1.75x, or about 2x, about 2.5x, about 3x, about 4x) of the same senotherapeutic agent(s) of the previous administration of an antisenescence treatment as compared to the amounts of the senotherapeutic agent(s) of the previous administration of an anti- senescence treatment.
  • a higher dosage amount e.g.
  • the revised antisenescence treatment can be a more frequent administration (e.g., once a week, once every two weeks, once a month, every 2 months, every 3 months, every 4 months, every 5 months, or every six months) of the same senotherapeutic agent(s) of the previous administration of an anti-senescence treatment as compared to the amounts of the senotherapeutic agent(s) of the previous administration of an anti-senescence treatment.
  • the revised antisenescence treatment can be designed to include one or more senotherapeutic agents that are different from the senotherapeutic agent(s) of the previous administration of an antisenescence treatment.
  • Any appropriate anti-senescence treatment, revised anti- senescence treatment, or senotherapeutic agent described herein can be administered to a mammal (e.g., a human) to inhibit or reduce cellular senescence within a mammal and/or to treat a mammal having a disease or disorder characterized by excess cellular senescence such as an age-related disease.
  • a mammal e.g., a human
  • an anti-senescence treatment e.g., one or more senotherapeutic agents
  • a composition e.g., a pharmaceutically acceptable composition
  • one or more senotherapeutic agents can be formulated together with one or more pharmaceutically acceptable carriers (additives), excipients, and/or diluents.
  • a pharmaceutically acceptable carrier, excipient, or diluent can be a naturally occurring pharmaceutically acceptable carrier, excipient, or diluent.
  • a pharmaceutically acceptable carrier, excipient, or diluent can be a non-naturally occurring (e.g., an artificial or synthetic) pharmaceutically acceptable carrier, excipient, or diluent.
  • pharmaceutically acceptable carriers, excipients, and diluents that can be used in a composition described herein include, without limitation, serum proteins (e.g., human serum albumin), water, polyethylene glycol, salts and electrolytes (e.g., phosphate salts, saline, protamine sulfate, and DMSO).
  • An anti-senescence treatment (e.g., one or more senotherapeutic agents) can be administered to a mammal (e.g., a human) by any appropriate route (e.g., oral, intranasal, inhalation, transdermal, and parenteral).
  • An anti-senescence treatment can be administered to a mammal locally or systemically.
  • an anti- senescence treatment can be administered locally by topical administration (e.g., as an ointment) to a mammal (e.g., a human).
  • an anti-senescence treatment can be administered locally by injection to a mammal (e.g., a human).
  • an anti-senescence treatment can be administered systemically by oral administration to a mammal (e.g., a human).
  • An anti-senescence treatment (e.g., one or more senotherapeutic agents) can be administered to a mammal (e.g., a human) in any appropriate amount (e.g., any appropriate dose).
  • An effective amount of an anti-senescence treatment can be any amount that reduces the level of PAPP- A polypeptides with the mammal being treated without producing significant toxicity to the mammal.
  • an effective amount e.g., an effective daily amount
  • an effective amount of dasatinib can be from about 1.5 milligrams per kilogram body weight (mg/kg) to about 3 mg/kg(e.g.
  • an effective amount (e.g., an effective daily amount) of quercetin can be from about 15 mg of quercetin per kg of body weight (mg/kg) to about 30 mg/kg (e.g., from about 15 mg/kg to about 25 mg/kg, from about 15 mg/kg to about 20 mg/kg, from about 15 mg/kg to about 18 mg/kg, from about 20 mg/kg to about 30 mg/kg, from about 25 mg/kg to about 30 mg/kg, from about 28 mg/kg to about 30 mg/kg, from about 18 mg/kg to about 25 mg/kg, from about 20 mg/kg to about 22 mg/kg, from about 18 mg/kg to about 20 mg/kg, from about 20 mg/kg to about 25 mg/kg, or from about 25 mg/kg to about 28 mg/kg).
  • an effective amount (e.g., an effective daily amount) of fisetin can be from about 20 mg of fisetin per kg of body weight (mg/kg) to about 100 mg/kg (e.g from about 20 mg/kg to about 80 mg/kg, from about 20 mg/kg to about 60 mg/kg, from about 20 mg/kg to about 50 mg/kg, from about 20 mg/kg to about 40 mg/kg, from about 20 mg/kg to about 30 mg/kg, from about 40 mg/kg to about 100 mg/kg, from about 60 mg/kg to about 100 mg/kg, from about 80 mg/kg to about 100 mg/kg, from about 30 mg/kg to about 90 mg/kg, from about 40 mg/kg to about 80 mg/kg, from about 50 mg/kg to about 70 mg/kg, from about 30 mg/kg to about 50 mg/kg, from about 40 mg/kg to about 60 mg/kg, from about 60 mg/kg to about 80 mg/kg, or from about 70 mg/kg to about
  • the effective amount can remain constant or can be adjusted as a sliding scale or variable dose depending on the mammal’s response to treatment.
  • Various factors can influence the actual effective amount used for a particular application. For example, the frequency of administration, duration of treatment, use of multiple treatment agents, route of administration, and/or severity of the disease or disorder characterized by excess cellular senescence (e.g., an age-related disease) in the mammal being treated may require an increase or decrease in the actual effective amount administered.
  • An anti-senescence treatment (e.g., one or more senotherapeutic agents) can be administered to a mammal (e.g., a human) at any appropriate frequency.
  • the frequency of administration can be any frequency that reduces the level of PAPP- A polypeptides with the mammal being treated without producing significant toxicity to the mammal.
  • the frequency of administration can be from about twice a day to about one every other day, from about once a day to about once a week, from about once a day to about once a month, from about once a week to about once a month, or from about twice a month to about once a month.
  • the frequency of administration can be daily for one or more (e.g., one, two, three, four, or more) consecutive days.
  • the frequency of administration can remain constant or can be variable during the duration of treatment.
  • various factors can influence the actual frequency of administration used for a particular application.
  • the effective amount, duration of treatment, use of multiple treatment agents, and/or route of administration may require an increase or decrease in administration frequency.
  • An anti-senescence treatment e.g., one or more senotherapeutic agents
  • An effective duration for administering or using an anti-senescence treatment can be any duration that reduces the level of PAPP- A polypeptides with the mammal being treated without producing significant toxicity to the mammal.
  • the effective duration can vary from several weeks to several months, from several months to several years, or from several years to a lifetime. Multiple factors can influence the actual effective duration used for a particular treatment.
  • an effective duration can vary with the frequency of administration, effective amount, use of multiple treatment agents, and/or route of administration.
  • methods for treating a mammal can include administering to the mammal one or more (e.g., one, two, three, four, or more) senotherapeutic agents as the sole active ingredient.
  • a composition containing one or more senotherapeutic agents can include the one or more senotherapeutic agents as the sole active ingredient in the composition for inhibiting or reducing cellular senescence.
  • methods for treating a mammal as described herein also can include administering to the mammal one or more (e.g., one, two, three, or more) additional agents used to treat a mammal having a disease or disorder characterized by excess cellular senescence such as an age-related disease and/or performing one or more (e.g., one, two, three, or more) therapies used to treat a mammal having a disease or disorder characterized by excess cellular senescence such as an age-related disease on the mammal.
  • additional agents used to treat a mammal having a disease or disorder characterized by excess cellular senescence
  • therapies used to treat a mammal having a disease or disorder characterized by excess cellular senescence such as an age-related disease on the mammal.
  • a combination therapy used to treat a mammal having a disease or disorder characterized by excess cellular senescence such as an age-related disease can include administering to the mammal (e.g., a human) one or more senotherapeutic agents as described herein and one or more (e.g., one, two, three, or more) additional agents used to treat a mammal having a disease or disorder characterized by excess cellular senescence such as an age-related disease.
  • an additional agent that can be used to treat a mammal having a disease or disorder characterized by excess cellular senescence such as an age-related disease can be an anti-fibrotic agent.
  • additional agents that can be administered to a mammal to treat a mammal having a disease or disorder characterized by excess cellular senescence such as an age-related disease include, without limitation, metformin, losartan, rapamycin, and any combinations thereof.
  • the one or more additional agents can be administered at the same time (e.g., in a single composition containing both one or more senotherapeutic agents and the one or more additional agents) or independently.
  • one or more senotherapeutic agents described herein can be administered first, and the one or more additional agents administered second, or vice versa.
  • a combination therapy used to treat a mammal having a disease or disorder characterized by excess cellular senescence such as an age-related disease can include administering to the mammal (e.g., a human) one or more (e.g., one, two, three, or more) senotherapeutic agents described herein and performing one or more (e.g., one, two, three, or more) additional therapies used to treat a mammal having a disease or disorder characterized by excess cellular senescence such as an age-related disease include, without limitation, lifestyle interventions, diet interventions, exercise, anti-smoking interventions, and/or stress reduction.
  • one or more senotherapeutic agents described herein are used in combination with one or more additional therapies used to treat a mammal having a disease or disorder characterized by excess cellular senescence such as an age-related disease
  • the one or more additional therapies can be performed at the same time or independently of the administration of one or more senotherapeutic agents described herein.
  • one or more senotherapeutic agents described herein can be administered before, during, or after the one or more additional therapies are performed.
  • a course of treatment can be monitored as described herein.
  • the levels of PAPP-A polypeptides within the mammal can be monitored over the course of treatment to determine whether or not the treatment is effective and/or remains effective over time.
  • Example 1 PAPP -A expression in senescent cells
  • Non-senescent human adipose-derived progenitors were isolated from subcutaneous adipose tissue from healthy kidney donors, and human umbilical vein endothelial cells (HUVECs) were made senescent by exposing the cells to 10 Gy ionizing radiation. Preadipocytes became senescent after 14 days, and HUVECs became senescent after 20 days. Senescence was assessed by staining for SA beta GAL activity. Sham irradiated cells were used as control. Cells were collected, RNA was isolated, and gene expression was measured by RT- PCR. Data were normalized to housekeeping gene TATA- binding protein expression and presented as a fold increase relative to the expression in nonsenescent cells.
  • Adipose tissue was cut into small pieces and washed with PBS 3 times. Adipose tissue was then cultured in medium containing 1 mM sodium pyruvate, 2 mM glutamine, MEM vitamins, MEM non-essential amino acids, and antibiotics with 20 pM Q + 1 pM D, 20 pM Fm or DMSO. After approximately 48 hours, the adipose explants were washed 3 times with PBS. Aliquots of adipose tissue were fixed for immunostaining or SA-Pgal assay.
  • CM conditioned medium
  • PAPP-A was measured in CM by ELISA and normalized to total protein in CM. Data are expressed as a ratio to vehicle-treated tissue.
  • MEN ⁇ SEM One -way ANOVA, P ⁇ 0.009, Tukey multiple comparisons *P ⁇ 0.048, **P ⁇ 0.008 ( Figure 2A).
  • adipose tissue was digested, and PAPP-A mRNA expression was measured by relative RT-PCR.
  • the housekeeping gene TBP was used as a control.
  • PAPPA-expression in treatment groups is expressed as a ratio to PAPPA-A level in vehicle-treated tissue.
  • MEN ⁇ SEM One -way ANOVA **P ⁇ 0.0018
  • Adipose tissue biopsies from greater omentum of obese human subjects were placed in organ culture dishes and were treated with vehicle or senolytic drugs (DQ or fisetin). After 48 hours of treatment, tissues were washed and provided with fresh media, and CM was collected after 24 hours (as described in Example 2). RNA was collected from cultured adipose tissue biopsies, and mRNA expression of pl 6, IL- la, IL-ip, and IL6 (known regulators of PAPPA-A expression) were measured by relative RT-PCR.
  • the heat map represents fold change of mRNA expression of senescence marker pl6 and known regulators of PAPPA-A expression (IL- la, IL-ip, and IL6) compared to those levels in the vehicle sample ( Figure 3).
  • a first blood sample is obtained from a human prior to the human being administered an anti-senescence treatment (e.g., prior to being administered one or more senotherapeutic agents), and a second blood sample is obtained from the human after the human has been administered the anti-senescence treatment.
  • an anti-senescence treatment e.g., prior to being administered one or more senotherapeutic agents
  • the first and second blood samples are assessed to determine whether or not the level of PAPP- A polypeptides present in the second blood sample was less than that of the first blood sample.
  • the anti-senescence treatment e g., one or more senotherapeutic agents
  • the human can continue with the same anti-senescence treatment.
  • the anti-senescence treatment e g., one or more senotherapeutic agents
  • the human can discontinue that particular anti- senescence treatment.
  • that human also can initiate an increased dosing regimen of that particular anti- senescence treatment or can initiate a different anti-senescence treatment.
  • a first urine sample is obtained from a human prior to the human being administered an anti-senescence treatment (e.g., prior to being administered one or more senotherapeutic agents), and a second urine sample is obtained from the human after the human has been administered the anti-senescence treatment.
  • an anti-senescence treatment e.g., prior to being administered one or more senotherapeutic agents
  • the first and second urine samples are assessed to determine whether or not the level of PAPP-A polypeptides present in the second urine sample was less than that of the first urine sample.
  • the anti-senescence treatment e g., one or more senotherapeutic agents
  • the human can continue with the same anti-senescence treatment.
  • the anti-senescence treatment e g., one or more senotherapeutic agents
  • the human can discontinue that particular anti- senescence treatment.
  • that human also can initiate an increased dosing regimen of that particular anti-senescence treatment or can initiate a different anti-senescence treatment.

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Abstract

Ce document concerne des procédés et des matériaux pour évaluer et/ou utiliser un ou plusieurs agents sénothérapeutiques. Par exemple, l'invention concerne des procédés et des matériaux pour déterminer l'efficacité d'un traitement anti-sénescence chez un mammifère (par exemple, un être humain) ainsi que des procédés et des matériaux pour traiter efficacement un mammifère avec un traitement anti-sénescence.
PCT/US2023/030229 2022-08-15 2023-08-15 Procédés et matériaux pour utiliser et évaluer des traitements anti-sénescence chez des mammifères WO2024039646A1 (fr)

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US20200188327A1 (en) * 2017-04-25 2020-06-18 Buck Institute For Research On Aging Formulations for extending lifespan and healthspan
US20200338039A1 (en) * 2017-12-01 2020-10-29 The Scripps Research Institute Methods and materials for assessing biological age and slowing the progress of excessive biological aging
WO2021257820A1 (fr) * 2020-06-17 2021-12-23 Mayo Foundation For Medical Education And Research Évaluation et traitement d'un vieillissement biologique

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180235957A1 (en) * 2014-01-28 2018-08-23 Buck Institute For Research On Aging Treatment of Ophthalmic Conditions by Selectively Removing Senescent Cells from the Eye
US20200188327A1 (en) * 2017-04-25 2020-06-18 Buck Institute For Research On Aging Formulations for extending lifespan and healthspan
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