A challenge of biomedical research is to compress the period of frailty and disability as people reach advanced age. Cellular senescence, the growth arrest that occurs when cells experience potentially oncogenic insults, has been proposed to contribute to age-related dysfunction. There is as yet no definitive evidence for this. To understand the role of senescent cells in age-related dysfunction, we created a mouse model from which p16-expressing senescent cells can be removed selectively. We devised mechanism-based interventions that interfere with the inflammatory senescence-associated secretory phenotype (SASP), which may be the basis of the inflammation that underlies many age-related diseases and frailty. We discovered a link between the SASP and immune system dysfunction, and found potential ways to break this link. Our unifying hypothesis is that preventing the accumulation of senescent cells or their effects can restore age-related decrements in function. We propose the following Specific Aims.
Aim 1 Eliminate senescent cells. We will use an innovative animal model from which we can selectively remove senescent, potentially cancerous cells to determine if this intervention attenuates development of age-related functional decrements and frailty and enhances health span.
Aim 2 Inhibit the SASP by manipulating Jak/Stat. We found the SASP is attenuated by inhibiting Jak/Stat, an intervention that dramatically reduces the frailty associated with cancer and hematological disorders. We will test the impact of this intervention on age-related dysfunction.
Aim 3 Inhibit the SASP by manipulating mTOR. We also found that inhibiting components of the mTOR pathway inhibits the SASP without interfering with the senescence-associated replicative arrest that defends against cancer. We will determine whether and how this inhibition reduces age-related dysfunction.
Aim 4 Break the link between the SASP and inflammasomal activation. We found the SASP activates the inflammasome, while inhibiting it restored immune function in old animals. We will test if inflammasome inhibitors reduce age-related senescent cell accumulation and dysfunction.
These Aims will be tested in four Subprojects supported by Administrative, Mouse Phenotyping and Pathological Assessment (MPPA), and Systems Biology/ Bioinformatics Cores. We will use innovative culture systems, novel animal models, and comprehensive health span phenotyping to test our hypothesis, focusing on frailty/muscle, metabolic/fat, skin, and immune function initially. Our approach will provide timely, innovative, and clinically relevant interventional results based on addressing the fundamental question of the role of cellular senescence that has remained unanswered for many years.
A challenge of biomedical research is to compress the period of frailty and disability as people reach advanced age. Senescent cells are cells that accumulate in old age and produce factors that cause tissue inflammation. This inflammation may be responsible for diseases and dysfunction in old age. We designed interventions to remove senescent cells or their effects, and will test if these restore function in old age.
|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|
|Stout, Michael B; Steyn, Frederik J; Jurczak, Michael J et al. (2017) 17?-Estradiol Alleviates Age-related Metabolic and Inflammatory Dysfunction in Male Mice Without Inducing Feminization. J Gerontol A Biol Sci Med Sci 72:3-15|
|Demaria, Marco; O'Leary, Monique N; Chang, Jianhui et al. (2017) Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discov 7:165-176|
|Palmer, Allyson K; Kirkland, James L (2016) Aging and adipose tissue: potential interventions for diabetes and regenerative medicine. Exp Gerontol 86:97-105|
|Zhu, Yi; Tchkonia, Tamara; Fuhrmann-Stroissnigg, Heike et al. (2016) Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 15:428-35|
|Comisford, Ross; Lubbers, Ellen R; Householder, Lara A et al. (2016) Growth Hormone Receptor Antagonist Transgenic Mice Have Increased Subcutaneous Adipose Tissue Mass, Altered Glucose Homeostasis and No Change in White Adipose Tissue Cellular Senescence. Gerontology 62:163-72|
|Xu, Ming; Tchkonia, Tamar; Kirkland, James L (2016) Perspective: Targeting the JAK/STAT pathway to fight age-related dysfunction. Pharmacol Res 111:152-154|
|Schafer, Marissa J; White, Thomas A; Evans, Glenda et al. (2016) Exercise Prevents Diet-Induced Cellular Senescence in Adipose Tissue. Diabetes 65:1606-15|
|Baker, Darren J; Childs, Bennett G; Durik, Matej et al. (2016) Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530:184-9|
|Campisi, Judith (2016) Cellular Senescence and Lung Function during Aging. Yin and Yang. Ann Am Thorac Soc 13:S402-S406|
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