p16 expression is required for the induction and maintenance of senescence

Senescence is a protective mechanism to prevent propagation of damage and cellular dysfunction. Expression of p16 is induced in senescent cells which become permanently growth arrested and resistant to apoptosis, and p16 expression is required for ongoing maintenance of the senescent state. Importantly, induction of senescence in immune cells governs the transition to and accumulation of senescence throughout the body, leading to organ function decline and appearance of chronic diseases associated with aging. Measurement of p16 in the immune system reflects senescent cell load.

A seminal paper from the lab of Dr. Ned Sharpless at the University of North Carolina described a clinically viable prototype for measuring senescence in human T-cells, creating a path for translating preclinical models of senescence-based disease into clinical tools to improve patient care. An improved version of Sharpless' prototype is a key part of Sapere Bio's technology for immune health bioprognostics.

Data firmly establishing p16 as an essential measure of senescence includes experimental animal models manipulating p16 expression, human GWAS studies, and Sapere Bio's prospective clinical studies.

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Senescence has dramatic effects on age-related disease and physical function in animal models

Transgenic mouse models have been developed linking the p16 promoter to reporter genes that allow selective induction and depletion of senescence (INK-ATTAC, p16-3MR).  Data from these models have been published in more than 30 papers establishing a role for senescence in onset and progression of nearly all age-related diseases including Alzheimer's disease, atherosclerosis, cancer, diabetes, kidney disease, and Parkinson's disease.

Beyond specific diseases, senescence imprints a decline in global physical function. Allogenic transplantation of senescent cells from old to young mice caused a dose-dependent reduction in muscle strength and walking speed, and increased risk of death by 5.2-fold. Clearance of senescent cells in p16-INK-ATTAC engineered mice restored age-related deficits in physical function.

Human disease susceptibility is associated with loci regulating senescence and immunity 

A meta-analysis of 372 Genome-Wide Association Studies (GWAS) that mapped 1,775 susceptibility SNPs to 105 human diseases showed two regions of strong multi-disease associations. One region was associated with autoimmune diseases and included the gene-rich major histocompatibility (MHC) locus on chromosome 6p21. The other included the locus for p16 (CDKN2A) on chromosome 9p21 and was associated with diseases of aging including atherosclerotic disease, type 2 diabetes, glaucoma, and cancer. These human genetic data identify p16 and immunity as key determinants of broad disease susceptibility and human health. 

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p16 gene expression in human T cells both reflects and predicts major clinical events

While undetectable in childhood, senescent cells accumulate in early adulthood and increase dramatically over a lifetime (>16-fold increase). Measurements of p16 in over 500 participants demonstrate a wide difference in senescence among individuals of the same age (Figure 1 and Liu et al 2009).  These individual differences represent biological stressors which vary in both intensity and duration and include nutrition, exercise, psychological stress, history of illness, chronic disease and infection, and medical interventions. Senescent cell burden integrates these exposures into a measure that both reflects and predicts major clinical events. For example, in donors who have been followed for over three years, p16 expression in donor #1 was stable, whereas, donor #2 exhibited a large spike in p16 coinciding with a significant immune event (Figure 2). p16 expression subsequently went down to a stable level. In patients for whom a major medical insult is imminent, senescence is prognostic (see leading clinical applications).

Figure 1. Large differences in senescence burden among same-aged individuals

Figure 2. Longitudinal measurements in individual donors reflect major health changes

Chemotherapy is an archetype exposure that demonstrates the power and clinical importance of senescence

Chemotherapy is an analogue where senescence and aging can be studied in response to a known biological insult of specific timing, dose, and intensity. Sustained, dose-dependent increases in senescence occur after chemotherapy in, for example, both breast cancer patients (Figure 3) and survivors of childhood cancer (Figures 4, 5). Further, young adult survivors of childhood cancer with elevated senescence experience physical frailty and cognitive challenges decades earlier than their peers, demonstrating that accelerated aging can happen even in early adulthood. Measurement of senescent cell burden longitudinally determines the rate of accelerated aging in individual patients which can inform ongoing care, including monitoring for long-term cardiovascular and cognitive issues. In addition, a pre-treatment snapshot of a patient's senescence burden reflects their physiologic reserve and ability to tolerate chemotherapy, and can predict specific chemotherapy-induced adverse events, including chemotherapy-induced peripheral neuropathy (CIPN)

Figure 3. Senescence increases in individual breast cancer patients following chemotherapy regardless of baseline level

Figure 4. Childhood cancer survivors have a higher burden of senescence than age-matched controls

Figure 5. Increases in senescence burden are dose-dependent, rising with increasing regimen intensity

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T cell senescence measurement is poised to frameshift clinical decision-making

Sapere Bio is translating this leading aging science into products that use senescent cell load measurement to inform clinical decisions. Our bioprognostics will offer a snapshot of a patient's aging before initiating treatment, and/or longitudinal measures to track and mitigate the effects of interventions on aging and long-term health. Each product is developed for a specific, high-value clinical decision.

Among Sapere products in development for cardiovascular and oncology indications, launch of AKI-Sapere for cardiac surgery is anticipated in 2022. Additional products are emerging from a rich portfolio of collaborations investigating how senescence and regulation of senescent cell load impact outcomes across many indications.

References

Liu et al 2009 "Expression of p16INK4A in peripheral blood T cells is a biomarker of human aging" Aging Cell 8:439-448

Tsygankov et al 2009 "A quantitative model for age-dependent expression of the p16INK4A tumor suppressor" PNAS 106(39):16562-16567

 

Animal models

Ogrodnik et al 2021 "Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice" Aging Cell 20(2):e13296

Bussian et al 2018 "Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline" Nature 562:578-582

Xu et al 2018 "Senolytics improve physical function and increase lifespan in old age" Nature Medicine 24:1246-1256

Demaria et al 2017 "Cellular senescence promotes adverse effects of chemotherapy and cancer relapse" Cancer Discovery 7(2):165-76

Baker et al 2016 "Naturally occurring p16INK4a-positive cells shorten healthy lifespan" Nature 530:184-89

Childs et al 2016 "Senescent intimal foam cells are deleterious at all stages of atherosclerosis" Science 354(6311):472-77

Baker et al 2011 "Clearance of p16INK4a-positive senescent cells delays aging-associated disorders" Nature 479:232-236

Human GWAS

Jeck et al 2012 "Review: A meta-analysis of GWAS studies and age-associated diseases" Aging Cell 11(5): 727-31

Clinical events and oncology

Muss et al 2020 "p16: a biomarker of aging and tolerance for cancer therapy" Translational Cancer Research 9(9):5732-42

Shachar et al 2020 "Effects of breast cancer adjuvant chemotherapy regimens on expression of the aging biomarker p16INK4a" JNCI Cancer Spectrum 4(6):pkaa082

Smitherman et al 2020 "Accelerated aging among childhood, adolescent, and young adult cancer survivors is evidenced by increased expression of p16INK4a and frailtyCancer 126(22):4975-4983

Wood et al 2016 "Chemotherapy and stem cell transplantation increase p16INK4a expression, a biomarker of T-cell aging" EBioMedicine 11:227-238

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