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 mechanismbased 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 hypotliesis 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 healthspan.
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 onage-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-associate 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 healthspan 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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
van Deursen, Jan M (2014) The role of senescent cells in ageing. Nature 509:439-46
Campisi, Judith; Robert, Ladislas (2014) Cell senescence: role in aging and age-related diseases. Interdiscip Top Gerontol 39:45-61
Escande, Carlos; Nin, Veronica; Pirtskhalava, Tamar et al. (2014) Deleted in Breast Cancer 1 regulates cellular senescence during obesity. Aging Cell 13:951-3
Campisi, Judith (2014) Cell biology: The beginning of the end. Nature 505:35-6
Zhu, Yi; Armstrong, Jacqueline L; Tchkonia, Tamara et al. (2014) Cellular senescence and the senescent secretory phenotype in age-related chronic diseases. Curr Opin Clin Nutr Metab Care 17:324-8
Stout, Michael B; Tchkonia, Tamara; Pirtskhalava, Tamar et al. (2014) Growth hormone action predicts age-related white adipose tissue dysfunction and senescent cell burden in mice. Aging (Albany NY) 6:575-86
Childs, Bennett G; Baker, Darren J; Kirkland, James L et al. (2014) Senescence and apoptosis: dueling or complementary cell fates? EMBO Rep 15:1139-53
Tchkonia, Tamara; Thomou, Thomas; Zhu, Yi et al. (2013) Mechanisms and metabolic implications of regional differences among fat depots. Cell Metab 17:644-56
Kirkland, James L (2013) Translating advances from the basic biology of aging into clinical application. Exp Gerontol 48:1-5
Baker, Darren J; Weaver, Robbyn L; van Deursen, Jan M (2013) p21 both attenuates and drives senescence and aging in BubR1 progeroid mice. Cell Rep 3:1164-74

Showing the most recent 10 out of 13 publications