Autophagy Somewhat Alleviates the Effects of Aging in the Heart

For many years now, since the first batch of single gene mutations that enhance longevity in short-lived laboratory species were discovered, the cellular maintenance processes of autophagy have occupied a central role in considerations of aging. The open access paper I'll link to today is focused on autophagy in the heart, and provides a good example of the reasons why autophagy is of interest to many of the researchers who search for ways to slow the progression of aging.

Aging is at root a process of damage accumulation. We are machines and we wear and break. Unlike the much simpler mechanical and electrical devices that surround us these days, however, our machinery has a great capacity for self-repair. The overwhelming majority of molecular damage and disarray that arises constantly in all of our cells is repaired very quickly. This makes the progression of damage over time a much more complicated and layered process than is the case in a car or a computer. You can look at the Fight Aging! FAQ for a high level summary, but that does no justice to the poorly understood intricacy of the ways in which the many forms of damage interact over time, and the way in which the diminished capacities or dysfunctions of specific organs and systems in the body feed into one another. Aging is perhaps as much a failure of repair systems as it is an accumulation of damage that cannot be repaired at all - though that certainly does exist in the form of cross-links that cannot be broken down, even in youth, to pick one example.

Autophagy is an important set of cellular repair systems, responsible for breaking down and recycling damaged structures, as well as some large molecules and metabolic wastes. It is a complicated arrangement of signals, detection of damage, markers for damage, processes for moving things around the cell, and specialized organelles that actually perform the dismantling. More autophagy is better for the obvious reason that it means there is less damage at any given point in time, so less of a chance for that damage to cause further issues. Many of the methods of extending life in laboratory species are associated with a higher level of autophagy in at least some tissue types. Calorie restriction, for example, the most well studied of all of the methods of somewhat slowing aging, appears to depend on autophagy for most of its benefits. Disable autophagy, and life is no longer extended by a diet lower in calories. One thing that has become very apparent from the past two decades of making various animals live modestly longer lives is that evolution has not selected for the optimal level of autophagy - or at least, longevity doesn't seem to be high on the list of factors determining that optimal level.

Thus many researchers are interested in producing some kind of therapy that can upregulate autophagy in humans, and for all the same reasons that many researchers want to build drugs that can mimic calorie restriction or mimic exercise. The idea is to modestly slow aging, as even a small gain would would produce enormous economic benefits when spread across the whole population. For me, this is thinking too small, and people should focus on repair and rejuvenation that can add decades for the same cost, but this SENS view of rejuvenation research is still fighting its way to the mainstream. Most researchers focus on slightly slowing aging as a goal, where they are interested in treating aging at all. Oddly, despite many years of working towards drug candidates that might induce greater autophagy, and a stream of research that always looks on the verge of going somewhere, there has been very little progress towards the clinic. The tone of the paper quoted below is very similar to work written ten or fifteen years ago, and yet the therapies are not here yet:

Aging and Autophagy in the Heart

Because the incidence of cardiac disease increases dramatically with age, it is important to understand the molecular mechanisms through which the heart becomes either more or less susceptible to stress. Cardiac aging is characterized by the presence of hypertrophy, fibrosis, and accumulation of misfolded proteins and dysfunctional mitochondria. Macroautophagy (hereafter referred to as autophagy) is a lysosome-dependent bulk degradation mechanism that is essential for intracellular protein and organelle quality control. Autophagy and autophagic flux are generally decreased in aging hearts, and murine autophagy loss-of-function models develop exacerbated cardiac dysfunction that is accompanied by the accumulation of misfolded proteins and dysfunctional organelles. On the contrary, stimulation of autophagy generally improves cardiac function in mouse models of protein aggregation by removing accumulated misfolded proteins, dysfunctional mitochondria, and damaged DNA, thereby improving the overall cellular environment and alleviating aging-associated pathology in the heart.

Because autophagy is downregulated with age and downregulation of autophagy promotes senescence of the heart, interventions to increase the level of autophagy may prevent or slow the progression of aging in the heart. Furthermore, considering the fact that cardiac aging is accompanied by the accumulation of insoluble polymeric materials, such as lipofuscin, and damaged organelles, it would seem to be advantageous to have a degradation mechanism with a large capacity. Interestingly, both calorie restriction (CR) and suppression of mTOR, interventions that alleviate the adverse effects of aging and increase lifespan, promote autophagy in many cell types and organs, even when autophagy is suppressed by aging. Importantly, CR has been shown to reduce age-related pathologies and diseases in animals. However, whether the beneficial effects of these interventions are mediated primarily through activation of autophagy in the heart requires further study.

Many other questions remain unanswered. First, it is unclear when the level of autophagy becomes significantly altered during the course of aging in the human heart. Currently, evaluating the level of autophagy and autophagic flux is challenging in the human heart in vivo. Developing convenient and reliable methods to accurately evaluate cardiac autophagy is essential. Second, more investigation is needed to elucidate the molecular mechanism by which autophagy or mitochondrial autophagy is regulated during the course of aging in the heart. Autophagy is regulated not only at the level of autophagosome formation but also at the levels of autophagosome-lysosome fusion and lysosomal degradation. In particular, how the function of lysosomes is affected by aging requires further investigation. Third, more investigation is needed to clarify the functional role of autophagy or mitophagy during cardiac aging. Currently, none of the available molecular interventions allow purely specific modification of either autophagy or mitophagy in mammalian cells. Currently, none of the available molecular interventions allow purely specific modification of either autophagy or mitophagy in mammalian cells. Whether protein aggregates, such as accumulated lipofuscin, are causatively involved in cardiac aging has not been formally addressed. Development of a more selective intervention or improvement of the selectivity by combining multiple interventions seems essential

Fourth, it is important to clarify the molecular mechanisms by which autophagy or mitophagy regulates cardiac aging. Although autophagy is generally thought to be a nonspecific mechanism of protein degradation, there is increasing evidence that some proteins may be specifically degraded. Fifth, most of the investigations reported to date focused only on autophagy in cardiomyocytes during aging. It is important to determine whether autophagy in other cell types, such as inflammatory cells, also affects cardiac aging and, if so, how these cells communicate with cardiomyocytes. Finally, it is essential to develop more convenient and specific interventions to normalize the level of autophagy in the heart during aging. Autophagy mediates many lifespan-extending and antisenescence mechanisms. Together with the recent advancement in understanding the molecular mechanisms of autophagy, investigating the role of autophagy/mitophagy during cardiac aging should eventually lead to the development of more efficient and specific interventions to slow senescence and increase stress resistance in the heart.


more destroying => more reproduction => more DNA damage => faster aging

Posted by: Martin S. at May 25th, 2016 1:19 AM

@Martin: The destroyed organelles (apart from mitochondria) don't reproduce and don't have DNA.

Posted by: Antonio at May 25th, 2016 2:41 AM

I meant full cells. But destroyed organelles must be replaced too and my guess is that DNA expression is required to build proteins organelles are made of.

Posted by: Martin S. at May 25th, 2016 7:16 AM

Autophagy doesn't apply to full cells.

Posted by: Antonio at May 25th, 2016 7:40 AM

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