An old proverb has it that what is not growing is dying. Recent findings regarding autophagy — a process by which cells turn over old proteins and clear cellular detritus — lead me to believe that what is not self-degrading is also dying.

A while back, we discussed a review that summarized the slowing of autophagy with increasing age. The efficiency of turnover decreases as an animal grows older, potentially creating a garbage catastrophe as increasing levels of damaged macromolecules further gum up the works. The upcoming issue of Molecular Aspects of Medicine has three reviews that treat various aspects of autophagy and aging in greater depth.

Terman et al. discuss the mechanisms by which failures of autophagy could contribute to cellular aging. They point out that post-mitotic cells (which don’t dilute old, worn-out parts by re-synthesis following cell division) would be particularly susceptible to the accumulation of damaged components. I would argue that this model of cellular aging is complementary to the story in mitotic cells, where we focus on cellular senescence as both a cell-autonomous and non-cell-autonomous source of tissue damage. Further, I would suggest that once a cell of a mitotic lineage (like a fibroblast or epithelial cell) becomes senescent, it would be subject to the same long-term accumulation of gunk as a terminally differentiated post-mitotic cell like a neuron.

… Damaged cellular components are not completely turned over by autophagy and other cellular repair systems, leading to a progressive age-related accumulation of biological “garbage” material, such as defective mitochondria, cytoplasmic protein aggregates and an intralysosomal undegradable material, lipofuscin. These changes primarily affect neurons, cardiac myocytes and other long-lived postmitotic cells that neither dilute this “garbage” by mitotic activity, nor are replaced by newly differentiated cells. Defective mitochondria are insufficient in ATP production and often generate increased amounts of reactive oxygen species … Lipofuscin-loaded lysosomes, in turn, poorly turn over mitochondria that gradually leads to the overload of long-lived postmitotic cells with “garbage” material, decreased adaptability and eventual cell death.

Alessio Donati points out that autophagy is stimulated by dietary restriction. This makes sense: autophagy is one of the ways that cells break down assembled components to replenish their supply of building blocks, which would be in short supply if the organism’s total intake is decreased. The article explores the possibility that some of the benefits of calorie restriction accrue from the accelerated clearance of damaged organelles:

Macroautophagy is a process that sequesters and degrades organelles and macromolecular constituents of cytoplasm for cellular restructuring and repair, and as a source of nutrients for metabolic use in early starvation. … It has been suggested that caloric restriction (CR) and disruption of insulin-like signals contrast the process of aging by prolonged stimulation of macroautophagy. According to this hypothesis, it is shown that life-long weekly administration of an anti-lipolytic drug decreases glucose and insulin levels, stimulates autophagy and intensifies anti-aging effects of submaximal CR.

Last but not least, Ettore Bergamini reviews the intriguing findings that autophagy can be artifically stimulated (by drugs that block lipolysis, which other authors suggest mimicks and/or intensifies calorie restriction); this idea is also treated in the Donati paper mentioned immediately above.

The process of ageing denotes a post-maturational deterioration of cells and organisms with the passage of time, an increased vulnerability to challenges and prevalence of age-associated diseases, and a decreased ability to survive. … It has been shown that autophagy is the only tier of defence against the accumulation of effete mitochondria and peroxisomes; that functioning of autophagy declines with increasing age and determinates cell and individual lifespan; that autophagy can be intensified by drugs; and that the pharmacological intensification of autophagy may be a big step towards retardation of ageing and prevention and therapy of age-associated diseases including neurodegeneration.

Taken together, the three reviews define an exciting direction for research to better understand the aging process and (especially per the last paper) to find ways to extend lifespan by using natural cellular defenses against accumulated damage.

It’s especially appealing because the simplest conceivable applications involve small-molecule drugs, so that no new gene-delivery technology is required. Furthermore, there are specific disease states that might benefit from increased autophagy, so drug development could proceed without the massive legal and practical issues attached to a de facto anti-aging therapy; lifespan extension could be an “off-label” application for the drugs once they were approved. Finally, unlike some other avenues of research, this approach doesn’t mess with the cell cycle, senescence, or tumor suppression — cellular pathways in which interference might have unacceptable consequences.

(Further commentary on these articles, published earlier this week, can be found at Longevity Meme)