Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice

Abstract

Senescent cells accumulate with age in vertebrates and promote aging largely through their senescence‐associated secretory phenotype (SASP). Many types of stress induce senescence, including genotoxic stress. ERCC1‐XPF is a DNA repair endonuclease required for multiple DNA repair mechanisms that protect the nuclear genome. Humans or mice with reduced expression of this enzyme age rapidly due to increased levels of spontaneous, genotoxic stress. Here, we asked whether this corresponds to an increased level of senescent cells. p16Ink4a and p21Cip1 mRNA were increased ~15‐fold in peripheral lymphocytes from 4‐ to 5‐month‐old Ercc1−/∆ and 2.5‐year‐old wild‐type (WT) mice, suggesting that these animals exhibit a similar biological age. p16Ink4a and p21Cip1 mRNA were elevated in 10 of 13 tissues analyzed from 4‐ to 5‐month‐old Ercc1−/∆ mice, indicating where endogenous DNA damage drives senescence in vivo. Aged WT mice had similar increases of p16Ink4a and p21Cip1 mRNA in the same 10 tissues as the mutant mice. Senescence‐associated β–galactosidase activity and p21Cip1 protein also were increased in tissues of the progeroid and aged mice, while Lamin B1 mRNA and protein levels were diminished. In Ercc1−/Δ mice with a p16Ink4a luciferase reporter, bioluminescence rose steadily with age, particularly in lung, thymus, and pancreas. These data illustrate where senescence occurs with natural and accelerated aging in mice and the relative extent of senescence among tissues. Interestingly, senescence was greater in male mice until the end of life. The similarities between Ercc1−/∆ and aged WT mice support the conclusion that the DNA repair‐deficient mice accurately model the age‐related accumulation of senescent cells, albeit six‐times faster.

Sex differences in cancer mechanisms

“…A recent study revealed that in both aged wild type mice (30 months) and progeroid mice, males express significantly greater levels of p16 and p21 mRNA in the liver, kidney, and spleen than age-matched females. This sex disparity was decreased in wild-type mice at the extremes of old age (35 months): p16 mRNA levels remained significantly lower in the liver and spleen of females compared to males, while p21 mRNA levels in the spleen were significantly greater in females than males [287]. These results suggest that males bear a larger load of senescent cells than females throughout aging, which may be influencing the increased male risk for various age-related pathologies, including cancer.…”

In vivo analysis of γH2AX+ cells in skeletal muscle from aged and obese humans

“…In satellite cells isolated from young (15‐24) and old (72‐80) humans, the rate of division, maximum number of divisions, p16 mRNA, and telomere length are not different 70,73 . Further, skeletal muscle from aged wild‐type and progeroid mice do not exhibit an increase in p16 or p21 expression 67 . However, although aging does not increase the absolute number of γH2AX+ satellite cells in human muscle, the percentage of satellite cells that are γH2AX+ is higher with age (3.5% compared to 7%), due to lower satellite cell abundance in aged muscle.…”

“…A recent paper by Yousefzadeh and colleagues 67 quantified p16 and p21 expression in various tissues using two animal models: 1) mice that developed senescence at a rapid rate (Ercc1 ‐/Δ ) and 2) young and old wild‐type mice. Relative to 10 other tissues, p16 and p21 expression in muscle tissues (heart, gastrocnemius, and quadriceps) were, overall, unchanged in the Ercc1 ‐/Δ model, whereas fat, aorta, kidney, liver, and large intestine had >10‐folder higher expression of p16 and p21 67 . Moreover, p16 and p21 expression were the lowest in the gastrocnemius and quadriceps, and were not higher in old wild‐type mice.…”

Exploring the Relevance of Senotherapeutics for the Current SARS-CoV-2 Emergency and Similar Future Global Health Threats

“…However, senescent fibroblasts, smooth muscle cells, and/or alveolar epithelial cells have been implicated in the etiology or progression of several human diseases, including chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and emphysema [39]. In mice, aging does not contribute to the induction of cellular senescence by cigarette smoke in the lung of a mouse model of COPD/emphysema [40], but other studies using aged wild type mice display an increase of p16Ink4a mRNA and senescence-associated-β-galactosidase (SA-β-Gal) activity in the lung compared to young controls [41,42]. The stimuli that drive lung cells into senescence are still incompletely understood and may include infection or inflammation due to infection.…”