Apoptosis and lifespan in a single-celled organism

The budding yeast Saccharomyces cerevisiae has been a valuable model system in biogerontology, dating back to the very earliest years of the modern synthesis of molecular genetics with the study of lifespan regulation. From yeast we first learned about the sirtuins, and it continues to teach us much about the mechanisms of lifespan extension by calorie restriction.

Aging in yeast can be studied in one of two ways: by focusing on the replicative lifespan (RLS), which is the number of times that a mother cell can bud to form a daughter; or on the chronological lifespan (CLS), which has to do with how long a cell can persist and maintain viability in a nondividing state. While there is some overlap between the genes regulating CLS and RLS, they are generally discussed as though they are distinct phenomena.

An under-appreciated feature of yeast aging is that, at the end of CLS or RLS, a yeast cell can die either by necrosis or by programmed cell death — i.e., apoptosis or something very much like it. That comes as a surprise to those of us who grew up thinking of apoptosis as a kind of “noble sacrifice” made by a damaged cell in the context of a tissue or organ: damage leads to cancer, but not if it leads to cell death first; hence, there’s a survival benefit to the organism if individual cells “voluntarily” die in response to certain types of stress. But with no body to protect, why would a single-celled organism undergo apoptosis?

The mechanisms and evolutionary ramifications of yeast apoptosis are the subject of a review by Rockenfeller and Madeo. For those of you who have followed this story for a while, Frank Madeo was the first author of the paper that identified caspase-like enzymes operating in yeast apoptosis; that manuscript was a worldwide journal-club favorite throughout the yeast and apoptosis fields back in the early years of the 21st century.

Apoptotic death of ageing yeast

Yeast has been a valuable model to study replicative and chronological ageing processes. Replicative ageing is defined by the number of daughter cells a mother can give birth to and hence reflects the ageing situation in proliferating cells, whereas chronological ageing is widely accepted as a model for postmitotic tissue ageing. Since both ageing forms end in yeast programmed death (necrotic and apoptotic), and abrogation of cell death by deletion of the apoptotic machinery or diminishment of oxidative radicals leads to longevity, apoptosis and ageing seem closely connected. This review focuses on ageing as a physiological way to induce yeast apoptosis, which unexpectedly defines apoptosis as a pro- and not an anti-ageing mechanism.

I take issue with the last sentence in the abstract, at least as it applies to the broader field of biogerontology. Very few of us in the mammalian aging field think of apoptosis as an “anti-aging” mechanism; rather, we see it as an tumor suppressor mechanism that has negative consequences on regenerative capacity. In other words, apoptosis in adult metazoans is an anti-cancer but pro-aging phenomenon.