Mild Mitochondrial Stress Found to Prevent Some of the Age-Related Declines in Cellular Maintenance in Nematodes
Hormesis is a near ubiquitous phenomenon in living organisms and their component parts: a little damage, a short or mild exposure to damaging circumstances, can result in a net benefit to health and longevity. Cells respond to damage or stress by increasing their self-repair efforts for some period of time, maintaining their function more effectively than would otherwise have been the case. At the high level, the outcomes of hormesis have been measured for a wide variety of stresses and systems, from individual cells to entire organisms. At the low level of specific biochemical processes and interaction of components inside the cell, there is a lot more mapping and cataloging to be accomplished, however.
The research noted below is an example of the this sort of exploration. It is an interesting study for demonstrating that some forms of stress response can turn back a fraction of the age-related decline in cellular maintenance processes, at least temporarily. It is well known that cellular maintenance falters in later life. This is in some cases a form of unhelpful reaction or side-effect caused by rising levels of damage and dysfunction, and in others it is a direct consequence of damage to the systems responsible for maintenance and repair. As an example of the second type, the lysosomes responsible for recycling broken molecules and structures in the cell can become clogged with rare, resilient waste compounds that they cannot process. The whole process of repair runs down when that happens.
The research here appears to touch on the first type of decline, demonstrating that controlling signals can be overridden to turn on the repair machinery once more. In the nematode worms the researchers work with, the species Caenorhabditis elegans, the result is a fair-sized increase in life span. Based on the results of numerous other interventions that increase the activities of cellular maintenance processes, this sort of outcome is expected. It is worth noting that very large increases of this nature in nematode life span - or indeed in any short-lived species - do not map to noteworthy increases in human life span. Our life spans are far less plastic in response to circumstances, despite benefiting from similar types of intervention. Calorie restriction is one of the better known ways to spur greater cellular maintenance activity, and while it certainly improves human health, it doesn't make us live significantly longer, as is the case in short-lived species.
Mitochondrial stress enhances resilience, protects aging cells and delays risk for disease
In a genetic study of the transparent roundworm C. elegans, a research team found that signals from mildly stressed mitochondria (the cellular source of energy) prevent the failure of protein-folding quality-control (proteostasis) machinery in the cytoplasm that comes with age. This, in turn, suppresses the accumulation of damaged proteins that can occur in degenerative diseases, such as Alzheimer's, Huntington's and Parkinson's diseases and amyotrophic lateral sclerosis (ALS).
"People have always known that prolonged mitochondrial stress can be deleterious. But we discovered that when you stress mitochondria just a little, the mitochondrial stress signal is actually interpreted by the cell and animal as a survival strategy. It makes the animals completely stress-resistant and doubles their lifespan. It's like magic. Our findings offer us a strategy for looking at aging in humans and how we might prevent or stabilize against molecular decline as we age. Our goal is not trying to find ways to make people live longer but rather to increase health at the cellular and molecular levels, so that a person's span of good health matches their lifespan."
The study builds on earlier work in which the researchers reported that the molecular decline leading to aging begins at reproductive maturity due to inhibitory signals from the germ line cells to other tissues to prevent induction of protective cell stress responses. In C. elegans, this is between eight and 12 hours of adulthood, yet the animal will typically live another three weeks. The researchers screened the roundworm's approximately 22,000 genes and identified a set of genes, called the mitochondrial electron transport chain (ETC), as a central regulator of age-related decline. Mild downregulation of ETC activity, small doses of xenobiotics and exposure to pathogens resulted in healthier animals, the researchers found.
Old age is the primary risk factor for many human diseases, but the overarching principles and molecular mechanisms that drive aging remain poorly understood. Aging has long been thought of as a stochastic process that is characterized by the gradual accumulation of cell damage. However, recent evidence suggests that aging arises, at least in part, from programmed events early in life that promote reproduction. In the nematode Caenorhabditis elegans, the ability to prevent metastable proteins from misfolding and aggregating fails early in adulthood, resulting in the appearance and persistence of protein aggregates in multiple tissues before animals have ceased reproduction.
Proteostasis is routinely maintained through the activity of constitutive and inducible stress response pathways. Among these, the transcription factor HSF-1 promotes the expression of molecular chaperones and enhances protein-folding capacity in the cytosol and nucleus through the heat shock response (HSR). During C. elegans adulthood, the HSR undergoes rapid repression as animals commence reproduction, thereby leaving cells vulnerable to environmental stress and proteostasis collapse well before overt signs of aging are distinguishable. This suggests that precise regulatory switches actively repress the HSR early in life as part of programs that promote reproduction at the cost of proteostasis.
To this end, we performed an unbiased genetic screen to identify genes whose knockdown maintains resistance to thermal stress and prevents repression of the HSR in reproductively active adults. We identified the mitochondrial electron transport chain (ETC) as a robust determinant of the timing and severity of the decline in the HSR and show that mild mitochondrial stress increases HSF-1 binding at target promoters, maintains the HSR, and preserves proteostasis in reproductively active animals. These beneficial effects were achieved without the severe physiological defects typically associated with impaired mitochondrial function, suggesting that modulation of mitochondrial activity is a physiologically relevant determinant of the timing of repression of the HSR and cytosolic proteostasis collapse with age.