Biology

More Data on the Tissue Specificity of Senescent Cell Accumulation with Age in Mice



As work progresses on the clinical development of senolytic therapies to selectively destroy harmful senescent cells in old tissues, it is becoming ever more necessary to have a better understanding of just how many senescent cells are present in any given tissue with age. Not all tissues acquire lingering populations of these cells at the same pace. Further, most current senolytic therapies are quite tissue specific, either because of the biodistribution characteristics of the drug, or because effectiveness varies in destroying senescent cells of different cell types.

Prioritization of development efforts requires some idea as to which tissues are more burdened by senescent cells, and thus more subject to the senescence-associated secretory phenotype in producing dysfunction and age-related disease, at least in the small molecule portion of the field. It is possible that Oisin Biotechnologies at least could just power through this challenge by saturating all tissues in the body with their non-toxic, highly selective suicide gene therapy vector. Brute force is sometimes an option.

Non-invasive ways of quantitatively assessing the presence of senescent cells in different tissues are also much needed, because we’d all like some idea as to how effective a given therapy might be. The dasatinib and quercetin senolytic combination is readily available, and you’ll bump into people who have used it at longevity industry conferences, but few of those have undergone the biopsies that are presently the only viable way to make before and after comparisons of senescent cell burden. Better methods are on the horizon, such as the circulating microRNA approach under development at TAmiRNA, but they are not on the market yet. These tools will be needed to enable a more rational design of the next generation of senolytics, and they would certainly help in the clinical development of the present generation of senolytics.

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

In this study, we provide a comprehensive measure of senescence in aged wild type (WT) mice. Senescence was quantified in multiple tissues, using numerous methods and numerous molecular endpoints, and we compared measures with that of young adult WT mice. We used this as a benchmark to determine whether Ercc1-/∆ mice, that exhibit accelerated aging, accumulate senescent cells in physiologically relevant tissues.

As measured by qRT-PCR and p16LUC signal, levels of p16Ink4a were significantly increased in aged WT mice compared with younger adult mice, as expected, p16Ink4a and p21Cip1 expression are found in peripheral T cells and numerous tissues (10 of 14 total tested) with the exception of heart and skeletal muscles. The differences in senescent cell burden in tissues could be reflective of different levels of genotoxic stress and/or different responses to that stress (e.g., selection of cell fate decisions: senescence or apoptosis). Near complete concordance was found between the expression of senescence markers in aged WT (2.5 years) and progeroid Ercc1-/∆ (4-5 month) mice, in terms of tissue specificity and expression levels.

The systemic burden of senescent cells was equivalent at the halfway point of lifespan in each of Ercc1-/∆ and WT mice, although the strains have vastly different lifespans. This supports the notion that senescent cell burden correlates with organismal health and may prove to be useful in predicting health span, or the remaining fraction of life that is disease-free. The data also support the conclusion that Ercc1-/∆ mice spontaneously develop senescent cells in the same tissues and at similar levels as WT mice, albeit more rapidly, supporting the notion that these animals represent a model of accelerated aging.

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