Deciphering Aging: Linking senescence with DNA Damage and the cell cycle

Participating Experts: Sheila A. Stewart, PhD (WUSTL) and James L. Kirkland, MD PhD, (Mayo Clinic)
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Download the Senescence Signaling Pathway Diagram: https://cst-science.com/tkawkd

Senescence describes the complex cellular response to stress that includes irreversible arrest of the cell cycle and thus prevention of the proliferation of defective or damaged cells. This effect makes senescence a key component in the body’s tumor suppression response and initialization of repair pathways, providing a health-promoting mechanism. Conversely, senescent cells can accumulate in the affected tissues of persons with age-related diseases such as dementias, arthritis, atherosclerosis, and others—such accumulation is considered a hallmark of aging that drives many age-related pathologies. These seemingly contradictory roles make cellular senescence an interesting research target for developing cancer suppression therapies as well as improving health maintenance and extending the human lifespan.

Table of Contents:
0:40 Welcome and overview
2:51 Sheila Stewart speaker profile
3:33 Age-related stromal changes drive tumorigenesis
5:12 Senescent fibroblasts promote tumorigenesis
7:28 Senescent cells express pro-tumorigenic factors
8:25 Senescent cells and immune cell infiltration are increased with age in human skin
10:51 Immune infiltration is increased in animal model of accelerated “aging” in the stromal compartment – the FASST mouse
12:02 Senescent fibroblasts direct the localization of immune cells within FASST skin
13:36 Senescent cells create an immunosuppressive, tumor permissive microenvironment
15:02 Does aging impact the premetastatic niche within the bone?
18:20 Ectopic expression of p27kip induces OB senescence and SASP expression
19:24 transgene activation leads to IL6 expression in osteoblasts
20:49 FASST mice with senescent osteoblasts have increased bone metastasis
23:34 Loss of stromal p38MAPK leads to reduced primary tumor growth
24:43 CAFs and senescent fibroblasts promote tumorigenesis through common mechanisms
27:39 Senescent cells express p38-MK2-dependent pro-tumorigenic factors
29:27 Tumor cells drive increase in osteoclasts, which drives increased tumor cell proliferation
31:23 p38MAPK and MK2 inhibition inhibits bone metastasis and preserves bone integrity
33:17 James Kirkland speaker profile
34:05 Aging, chronic disease, and senolytic drugs
38:24 Senescence overview
40:53 Senescent cells accumulate in human adipose tissue with aging
42:28 Transplanting senescent cells into knees causes osteoarthritis-like joint destruction
45:05 Transplanted senescent cells spread senescence to host cells
45:50 networks of anti-apoptotic regulators confer resistance to apoptosis in senescent cells
49:35 Senolytic agents, senescent cell anti-apoptotic pathways (SCAPs), and cell types targeted
51:25 D+Q clears transplanted luciferase-expressing senescent preadipocytes
51:51 D+Q is senolytic in freshly-isolated human adipose tissue
53:20 Senolytics delay neurologic dysfunction in progeroid mice
54:14 Senolytics alleviate Alzheimer’s-like changes in Tau+ mice
56:01 A single dose of senolytics alleviates radiation-induced gait disturbance for 7 months
58:12 Senolytics reduce intimal calcification in ApoE / atherosclerotic mice
59:42 Senolytics decrease frailty and extend lifespan in old mice
1:01:08 Clinical scenarios for testing agents that target aging processes

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