Aging is the leading risk factor for most of the chronic diseases that account for the bulk of morbidity, mortality, and health costs. It may be feasible to delay age-related diseases as a group by targeting aging mechanisms, such as cellular senescence. We discovered that removing senescent cells enhances healthspan in progeroid INK-ATTAC mice expressing a drug-inducible suicide transgene in senescent cells. Our hypothesis is that pharmacological targeting of survival pathways in senescent cells can be translated into interventions that enhance healthspan. It is crucial to develop compounds that selectively target senescent cells -senolytic agents. Senescent cells are resistant to apoptosis, so we used bioinformatics and RNA interference approaches to identify survival pathways needed for senescent cell survival. We found that prototype senolytic agents targeting these pathways selectively eliminated senescent cells and alleviated a range of aging- and senescence-related phenotypes.
Aim 1 is to delineate mechanisms and effects of targeting senescent cells in vitro. We will dissect senescent cell survival mechanisms and senolytic pathways by uncovering new drug targets needed for senescent cell survival by further tracing the pathways through which our current agents exert senolytic effects. We found that genetic and pharmacological targeting of senescent cells both remove ~30-70% -but not all- senescent cells, yet phenotypes are alleviated. Thus, we suspect there are senescent cell subtypes that differ in susceptibility to removal and contribution to adverse phenotypes. We will determine how senescent cells that are eliminated differ from remaining senescent cells in vitro and in vivo. We will leverage our finding that senescent cells arising from different cell types vary in susceptibiity to different senolytic agents to discover cell type-specific senolytic pathways. We will test effecs of combinations of senolytic agents that act through distinct pathways.
Aim 2 is to test effectiveness of senolytic agents in clearing senescent cells in vivo. We will compare clearance from different tissues by our senolytic agents in rodents. We found these agents alleviate cardiac dysfunction, impaired vascular reactivity, immobility, frailty, neurologic deficits, osteoporosis, and diabetes in mouse models. We will gauge the strength of associations between senescent cell clearance and phenotype resolution in mice treated with senolytic agents and a novel senescent preadipocyte transplantation model. We will test the extent to which agents exert phenotypic effects by clearing senescent cells vs. effects on non-senescent cells.
Aim 3 is to determine the impact of senolytic agents on healthspan phenotypes. Effects of senolytic agents and combinations will be tested on aging metabolic, cardiovascular, lung, muscle, cognitive, and immune phenotypes and in models relevant to chronic diseases. Effects on late life survival in mice will be ascertained. We will test if senolytic agents phenocopy or ar additive (epistasis) to effects of suicide gene-mediated senescent cell clearance. Development of drugs that eliminate senescent cells selectively could lead to a transformation in treating multiple age-related disorders.
Aging is the leading risk factor for most of the chronic diseases that account for the bulk of morbidity, mortality, and health costs. It may be feasible to delay age-related diseases as a group by targeting an aging mechanism, cellular senescence. Senescent cells are cells that have stopped dividing and that cause tissue dysfunction. They accumulate with aging and age-related chronic diseases. We discovered that removing senescent cells enhances healthy lifespan in genetically modified mice. Our goal now is to develop drugs that selectively target senescent cells -senolytic agents. We developed prototype senolytic agents and discovered they ameliorate a range of senescence-related disorders in animals. We will now determine how they kill senescent cells in order to make further senolytic drugs. We will characterize the types of senescent cells they kill so we can develop agents that work on the most damaging senescent cells in specific tissues. This will enable us develop agents for treating particular age-related disorders. The impact of senolytic agents on lifespan will be tested in animals. Development of drugs that eliminate senescent cells is of potentially profound significance. It is possible that senolytic agents could transform management of multiple age-related disorders.
| Xu, Ming; Pirtskhalava, Tamar; Farr, Joshua N et al. (2018) Senolytics improve physical function and increase lifespan in old age. Nat Med 24:1246-1256 |
| Khosla, Sundeep; Farr, Joshua N; Kirkland, James L (2018) Inhibiting Cellular Senescence: A New Therapeutic Paradigm for Age-Related Osteoporosis. J Clin Endocrinol Metab 103:1282-1290 |
| Moncsek, Anja; Al-Suraih, Mohammed S; Trussoni, Christy E et al. (2018) Targeting senescent cholangiocytes and activated fibroblasts with B-cell lymphoma-extra large inhibitors ameliorates fibrosis in multidrug resistance 2 gene knockout (Mdr2-/- ) mice. Hepatology 67:247-259 |
| Hadley, Evan C; Kuchel, George A; Newman, Anne B et al. (2017) Report: NIA Workshop on Measures of Physiologic Resiliencies in Human Aging. J Gerontol A Biol Sci Med Sci 72:980-990 |
| Fuhrmann-Stroissnigg, Heike; Ling, Yuan Yuan; Zhao, Jing et al. (2017) Identification of HSP90 inhibitors as a novel class of senolytics. Nat Commun 8:422 |
| Niedernhofer, L J; Kirkland, J L; Ladiges, W (2017) Molecular pathology endpoints useful for aging studies. Ageing Res Rev 35:241-249 |
| Kirkland, James L; Tchkonia, Tamara; Zhu, Yi et al. (2017) The Clinical Potential of Senolytic Drugs. J Am Geriatr Soc 65:2297-2301 |
| Xu, Ming; Bradley, Elizabeth W; Weivoda, Megan M et al. (2017) Transplanted Senescent Cells Induce an Osteoarthritis-Like Condition in Mice. J Gerontol A Biol Sci Med Sci 72:780-785 |
| Zhu, Yi; Doornebal, Ewald J; Pirtskhalava, Tamar et al. (2017) New agents that target senescent cells: the flavone, fisetin, and the BCL-XLinhibitors, A1331852 and A1155463. Aging (Albany NY) 9:955-963 |
| Kandhaya-Pillai, Renuka; Miro-Mur, Francesc; Alijotas-Reig, Jaume et al. (2017) TNF?-senescence initiates a STAT-dependent positive feedback loop, leading to a sustained interferon signature, DNA damage, and cytokine secretion. Aging (Albany NY) 9:2411-2435 |
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