Fight Aging!

In today's open access paper, the authors report on inroads in counting senescent immune cells in blood samples from human patients of different ages. Accurate determination of senescence status isn't cut and dried for many types of immune cell, but the researchers believe they have produced good numbers for cytotoxic T cells, showing that older people have many more senescent cells in this category. I'd like to see more of this sort of research, establishing some sort of baseline of expectations for levels of cellular senescence in various tissues by age, leading towards assays that can be used to directly the measure the outcome of treatment with senolytic drugs to selectively destroy senescent cells.

The results here suggest surprisingly high levels of cellular senescence in some important immune cell populations, more than half of the cells in a sample being senescent by the criteria used. In the broader context, it would make sense for numbers to be high relative to tissues. After the thymus atrophies significantly in late life, near all new T cells - needed to maintain the observed constant T cell population across a lifetime - are created by replication of existing T cells. Eventually cells hit the Hayflick limit and either self-destruct or become senescent.

Will treatment with senolytics produce benefits to immune function in this scenario? It will kill senescent T cells, and more cells will become senescent in the course of replicating to make up the numbers. The outcome will most likely be a lower count of senescent immune cells than existed prior to treatment, and the benefits of clearing senescent cells throughout the body should be sizable, but it is something to consider. Replication stress on the immune system is to be avoided if possible. One would have to test this scenario in larger mammals than mice: one big difference between mice and people is that mice do not rely on replication of existing T cells to maintain overall T cell population size, so there is little to be learned from existing mouse data.

Senescence-associated β-galactosidase reveals the abundance of senescent CD8+ T cells in aging humans

Aging leads to a progressive functional decline of the immune system, rendering the elderly increasingly susceptible to disease and infection. The degree to which immune cell senescence contributes to this decline remains unclear, however, since markers that label immune cells with classical features of cellular senescence accurately and comprehensively have not been identified.

Using a second-generation fluorogenic substrate for β-galactosidase and multi-parameter flow cytometry, we demonstrate here that peripheral blood mononuclear cells (PBMCs) isolated from healthy humans increasingly display cells with high senescence-associated β-galactosidase (SA-βGal) activity with advancing donor age. The greatest age-associated increases were observed in CD8+ T-cell populations, in which the fraction of cells with high SA-βGal activity reached average levels of 64% in donors in their 60s. CD8+ T cells with high SA-βGal activity, but not those with low SA-βGal activity, were found to exhibit features of telomere dysfunction-induced senescence and p16-mediated senescence, were impaired in their ability to proliferate, developed in various T-cell differentiation states, and had a gene expression signature consistent with the senescence state previously observed in human fibroblasts.

Based on these results, we propose that senescent CD8+ T cells with classical features of cellular senescence accumulate to levels that are significantly higher than previously reported and additionally provide a simple yet robust method for the isolation and characterization of senescent CD8+ T cells with predictive potential for biological age.