Senescent Cells and the SASP: The Aging Cells That Refuse to Leave

Key Takeaways:

• Senescent cells have permanently stopped dividing yet resist the programmed death that would normally clear them, and rather than sitting quietly they secrete a senescence-associated secretory phenotype, or SASP, rich in inflammatory factors such as interleukin-6 and interleukin-8.
• In progeroid mice, selectively eliminating p16Ink4a-positive senescent cells delayed age-related decline in fat, skeletal muscle, and the eye, and clearing them late in life slowed disorders that were already under way.
• Exercise prevented the build-up of senescent cells and their secretory signature in the visceral fat of mice fed a fast-food diet; senolytic drugs in humans remain experimental, supported so far only by small pilot studies.

September is Healthy Aging Month, and one of the more useful ideas to come out of aging biology in the last fifteen years is that some of our cells age badly in a very specific way. Senescent cells are cells that have hit a hard stop. Faced with enough DNA damage, critically shortened telomeres, or an activated cancer-driving gene, a cell switches on cell-cycle brakes such as p16INK4a and p21 and permanently withdraws from division. That is a genuinely protective move, because a damaged cell that can no longer divide cannot become a tumor, and cellular senescence is one of the body’s frontline defenses against cancer. The trouble begins with what happens next. A cell in this state does not quietly disappear. It resists apoptosis, the tidy self-destruct program that removes most damaged cells, and it lingers — and with age, as the immune system’s clearance slows and damage accumulates, senescent cells build up in fat, muscle, skin, blood vessels, and other tissues.

Lingering would be harmless if these cells were inert, and they are not. When human cells are pushed into senescence by genotoxic stress, they begin, over several days, to secrete a large and remarkably consistent mix of inflammatory and tissue-remodeling factors, the senescence-associated secretory phenotype. The same signature appears in fibroblasts, in epithelial cells, and in tumor cells from patients treated with DNA-damaging chemotherapy. It is not merely background noise: in cultured premalignant epithelial cells, the SASP drove a shift toward invasive, mesenchymal behavior through a paracrine mechanism that depended largely on interleukin-6 and interleukin-8. In other words, one senescent cell can change the behavior of its healthy neighbors. That is the core of the argument that senescence contributes to aging itself, and it was tested directly. Using a transgene that kills p16Ink4a-positive cells on command, researchers cleared senescent cells from rapidly aging mice; lifelong clearance delayed the onset of age-related disease in adipose tissue, skeletal muscle, and the eye, and clearance started late in life slowed conditions that were already established.

Can you reduce senescent cells as you age?

In animals, yes, by two very different routes, and in people the honest answer is still unfolding. The pharmacologic route follows from the fact that senescent cells survive by leaning on pro-survival networks. Transcript analysis showed those networks — including BCL-xL, PI3K-delta, and ephrin signaling — switched up in senescent cells, and drugs aimed at them, notably the combination of dasatinib and quercetin, selectively killed senescent cells and reduced senescent burden in aged mice, improving cardiac and vascular function after a single dose. These drugs are called senolytics. The first human study, however, was a fourteen-person, open-label pilot in idiopathic pulmonary fibrosis designed mainly to test feasibility; it found the regimen could be delivered and was followed by improved physical function, but without a control group it cannot establish benefit, and it is not a basis for anyone to self-prescribe a leukemia drug or high-dose quercetin as an anti-aging strategy. The second route is far less exotic. In mice fed a fast-food diet, senescent cells and their SASP piled up in visceral fat, and regular exercise prevented that accumulation; exercise begun after long-term poor diet reduced senescence markers that had already built up. The mechanism is still being mapped in humans, but the practical overlap is reassuring: the habits that keep visceral fat down and muscle working — consistent aerobic exercise, resistance training, and a diet built on whole plant foods — are also the ones most likely to keep the senescent-cell burden, and the inflammation it broadcasts, from quietly climbing with each decade.

References:

1. Coppé, J. P., Patil, C. K., Rodier, F., Sun, Y., Muñoz, D. P., Goldstein, J., et al. (2008). Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biology, 6(12), 2853-2868.
2. Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., van de Sluis, B., et al. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236.
3. Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., et al. (2015). The Achilles’ heel of senescent cells: From transcriptome to senolytic drugs. Aging Cell, 14(4), 644-658.
4. Justice, J. N., Nambiar, A. M., Tchkonia, T., LeBrasseur, N. K., Pascual, R., Hashmi, S. K., et al. (2019). Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine, 40, 554-563.
5. Schafer, M. J., White, T. A., Evans, G., Tonne, J. M., Verzosa, G. C., Stout, M. B., et al. (2016). Exercise prevents diet-induced cellular senescence in adipose tissue. Diabetes, 65(6), 1606-1615.