Targeting Cellular Senescence for Age-Related Diseases: Path to Clinical Translation

Summary: Beyond the palliative reach of today’s medicines, medical therapies of tomorrow aim to treat the root cause of age-related diseases by targeting fundamental aging mechanisms. Pillars of aging include, among others, genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, dysregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. The unitary theory of fundamental aging processes posits that by targeting one fundamental aging process, it may be feasible to impact several or all others given its interdependence. Indeed, pathologic accumulation of senescent cells is implicated in chronic diseases and age-associated morbidities, suggesting that senescent cells are a good target for whole-body aging intervention. Preclinical studies using senolytics, agents that selectively eliminate senescent cells, and senomorphics, agents that inhibit production or release of senescence-associated secretory phenotype factors, show promise in several aging and disease preclinical models. Early clinical trials using a senolytic combination (dasatinib and quercetin), and other senolytics including flavonoid, fisetin, and BCL-xL inhibitors, illustrate the potential of senolytics to alleviate age-related dysfunction and diseases including wound healing. Translation into clinical applications requires parallel clinical trials across institutions to validate senotherapeutics as a vanguard for delaying, preventing, or treating age-related disorders and aesthetic aging.

[1]  J. Campisi,et al.  The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice , 2021, Nature Metabolism.

[2]  J. Kirkland,et al.  Strategies for late phase preclinical and early clinical trials of senolytics , 2021, Mechanisms of Ageing and Development.

[3]  G. Kuchel,et al.  Strategies for targeting senescent cells in human disease , 2021, Nature Aging.

[4]  J. Kirkland,et al.  Impact of Senescent Cell Subtypes on Tissue Dysfunction and Repair: Importance and Research Questions , 2021, Mechanisms of Ageing and Development.

[5]  J. Gil,et al.  Senescence and the SASP: many therapeutic avenues , 2020, Genes & development.

[6]  M. Quante,et al.  Senolytics prevent mt-DNA-induced inflammation and promote the survival of aged organs following transplantation , 2020, Nature Communications.

[7]  L. Nicholas Geriatric dermatology. , 2020, The Journal of the Medical Society of New Jersey.

[8]  J. Kirkland,et al.  Senolytic drugs: from discovery to translation , 2020, Journal of internal medicine.

[9]  Amanda R. Kulick,et al.  Senolytic CAR T cells reverse senescence-associated pathologies , 2020, Nature.

[10]  J. Elisseeff,et al.  Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity , 2020, Nature Communications.

[11]  M. Mildner,et al.  Organotypic human skin culture models constructed with senescent fibroblasts show hallmarks of skin aging , 2020, npj Aging and Mechanisms of Disease.

[12]  J. Kirkland,et al.  Discovery, development, and future application of senolytics: theories and predictions , 2020, The FEBS journal.

[13]  Shahrukh K Hashmi,et al.  Corrigendum to ‘Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease’ EBioMedicine 47 (2019) 446–456 , 2020, EBioMedicine.

[14]  H. Nakagami Cellular senescence and senescence‐associated T cells as a potential therapeutic target , 2019, Geriatrics & gerontology international.

[15]  Shahrukh K Hashmi,et al.  Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease , 2019, EBioMedicine.

[16]  A. Alimonti,et al.  Cellular Senescence: Aging, Cancer, and Injury. , 2019, Physiological reviews.

[17]  A. Bhushan,et al.  Activation of the mTORC1/PGC-1 axis promotes mitochondrial biogenesis and induces cellular senescence in the lung epithelium. , 2019, American journal of physiology. Lung cellular and molecular physiology.

[18]  S. Kritchevsky,et al.  Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study , 2019, EBioMedicine.

[19]  Jun-Ping Liu,et al.  Roles of Telomere Biology in Cell Senescence, Replicative and Chronological Ageing , 2019, Cells.

[20]  N. Fortunel,et al.  Age-related evolutions of the dermis: Clinical signs, fibroblast and extracellular matrix dynamics , 2019, Mechanisms of Ageing and Development.

[21]  I. Ovsyannikova,et al.  Senescent cell clearance by the immune system: Emerging therapeutic opportunities. , 2018, Seminars in immunology.

[22]  J. Kirkland,et al.  Aging, Cell Senescence, and Chronic Disease: Emerging Therapeutic Strategies. , 2018, JAMA.

[23]  P. Robbins,et al.  Fisetin is a senotherapeutic that extends health and lifespan , 2018, EBioMedicine.

[24]  D. Torella,et al.  Aged‐senescent cells contribute to impaired heart regeneration , 2018, bioRxiv.

[25]  F. Mulero,et al.  A versatile drug delivery system targeting senescent cells , 2018, EMBO molecular medicine.

[26]  M. Demaria,et al.  Hallmarks of Cellular Senescence. , 2018, Trends in cell biology.

[27]  L. Feng,et al.  Senescent cells re‐engineered to express soluble programmed death receptor‐1 for inhibiting programmed death receptor‐1/programmed death ligand‐1 as a vaccination approach against breast cancer , 2018, Cancer science.

[28]  D. Allison,et al.  Senolytics Improve Physical Function and Increase Lifespan in Old Age , 2018, Nature Medicine.

[29]  J. Gil,et al.  Mechanisms and functions of cellular senescence. , 2018, The Journal of clinical investigation.

[30]  M. Giacca,et al.  Identification of HSP90 inhibitors as a novel class of senolytics , 2017, Nature Communications.

[31]  L. Niedernhofer,et al.  The Clinical Potential of Senolytic Drugs , 2017, Journal of the American Geriatrics Society.

[32]  Yossi Ovadya,et al.  Quantitative identification of senescent cells in aging and disease , 2017, Aging cell.

[33]  J. Kirkland,et al.  Cellular Senescence: A Translational Perspective , 2017, EBioMedicine.

[34]  Wiggert A. van Cappellen,et al.  Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging , 2017, Cell.

[35]  P. Robbins,et al.  New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463 , 2017, Aging.

[36]  Daohong Zhou,et al.  Discovery of piperlongumine as a potential novel lead for the development of senolytic agents , 2016, Aging.

[37]  S. Austad,et al.  Barriers to the Preclinical Development of Therapeutics that Target Aging Mechanisms , 2016, The journals of gerontology. Series A, Biological sciences and medical sciences.

[38]  Cory B. Giles,et al.  Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors , 2016, Aging cell.

[39]  W. Vainchenker,et al.  P53 activation inhibits all types of hematopoietic progenitors and all stages of megakaryopoiesis , 2016, Oncotarget.

[40]  J. Kirkland Translating the Science of Aging into Therapeutic Interventions. , 2016, Cold Spring Harbor perspectives in medicine.

[41]  A. Pezeshki,et al.  Naturally occurring p16Ink4a-positive cells shorten healthy lifespan , 2016, Nature.

[42]  M. Jensen,et al.  Targeting senescent cells enhances adipogenesis and metabolic function in old age , 2015, eLife.

[43]  N. Sharpless,et al.  Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice , 2015, Nature Medicine.

[44]  N. LeBrasseur,et al.  The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs , 2015, Aging cell.

[45]  Dolores Diaz,et al.  Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy , 2015, Science Translational Medicine.

[46]  J. Praestgaard,et al.  mTOR inhibition improves immune function in the elderly , 2014, Science Translational Medicine.

[47]  J. Hoeijmakers,et al.  An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. , 2014, Developmental cell.

[48]  E. Schadt,et al.  Geroscience: Linking Aging to Chronic Disease , 2014, Cell.

[49]  J. Kirkland,et al.  Cellular senescence and the senescent secretory phenotype in age-related chronic diseases , 2014, Current opinion in clinical nutrition and metabolic care.

[50]  Manuel Serrano,et al.  The Hallmarks of Aging , 2013, Cell.

[51]  J. Campisi,et al.  Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. , 2013, The Journal of clinical investigation.

[52]  J. Kirkland Translating advances from the basic biology of aging into clinical application , 2013, Experimental Gerontology.

[53]  D. Lewis,et al.  Reversing the aging stromal phenotype prevents carcinoma initiation , 2011, Aging.

[54]  W. Wilson,et al.  Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. , 2010, The Lancet. Oncology.

[55]  J. Campisi,et al.  Protocols to detect senescence-associated beta-galactosidase (SA-βgal) activity, a biomarker of senescent cells in culture and in vivo , 2009, Nature Protocols.

[56]  Yves Pommier,et al.  γH2AX and cancer , 2008, Nature Reviews Cancer.

[57]  Jill P. Mesirov,et al.  GSEA-P: a desktop application for Gene Set Enrichment Analysis , 2007, Bioinform..

[58]  A. Terzic,et al.  Individualized Medicine and the Imperative of Global Health , 2007, Clinical pharmacology and therapeutics.

[59]  D. Cortese,et al.  A Vision of Individualized Medicine in the Context of Global Health , 2007, Clinical pharmacology and therapeutics.

[60]  Stephanie Studenski,et al.  Geriatric Syndromes: Clinical, Research, and Policy Implications of a Core Geriatric Concept , 2007, Journal of the American Geriatrics Society.

[61]  N. Sharpless,et al.  Ink4a/Arf expression is a biomarker of aging. , 2004, The Journal of clinical investigation.

[62]  Contet‐Audonneau,et al.  A histological study of human wrinkle structures: comparison between sun‐exposed areas of the face, with or without wrinkles, and sun‐protected areas , 1999, The British journal of dermatology.

[63]  J. Campisi The role of cellular senescence in skin aging. , 1998, The journal of investigative dermatology. Symposium proceedings.

[64]  C Roskelley,et al.  A biomarker that identifies senescent human cells in culture and in aging skin in vivo. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[65]  E. Wang,et al.  Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved. , 1995, Cancer research.

[66]  L. Hayflick THE LIMITED IN VITRO LIFETIME OF HUMAN DIPLOID CELL STRAINS. , 1965, Experimental cell research.

[67]  N. LeBrasseur,et al.  Cellular Senescence and the Biology of Aging, Disease, and Frailty. , 2015, Nestle Nutrition Institute workshop series.

[68]  F W Pirruccello,et al.  Plastic and reconstructive surgery. , 1967, IMJ. Illinois medical journal.