Failing Mitophagy in the Aging Heart
Every cell contains hundreds of mitochondria, bacteria-like organelles that work to provide the cell with adenosine triphosphate (ATP), a chemical energy store molecule to power cellular biochemistry. With age, mitochondrial function falters throughout the body. This may be largely a consequence of failing mitophagy, a form of the cellular maintenance process of autophagy that is responsible for destroying worn and damaged mitochondria. In tissues with high energy demands, such as the heart, this loss of function is a sizable contributing factor in the development of age-related disease.
At present the research and development communities are still in the comparatively early stages in the production of ways to address this problem. Both upregulation of NAD+ in mitochondria and delivery of mitochondrially targeted antioxidants appear to somewhat reverse the loss of mitophagy, and thus improve mitochondrial function, but the outcomes in human trials and animal models are not reliably positive at this point in time. The effect size of these treatments is likely not large enough. A range of better approaches lie ahead, such as periodic delivery of large numbers of whole mitochondria harvested from cell cultures, but even these classes of treatment do not address the root causes of mitochondrial decline.
Researchers have identified a number of proteins important to mitophagy wherein expression changes with age, but connecting these changes to the underlying damage that causes aging is yet to be accomplished. Repairing forms of molecular damage known to cause aging and observing the results in mitochondria is probably a faster strategy than trying to work backwards from the present understanding of disrupted regulation of mitophagy. This sort of approach could be carried out today for clearance of senescent cells, and some forms of stem cell transplantation, but most forms of cell and tissue damage thought to cause aging still require potential therapies to be further developed.
The Aging Heart: Mitophagy at the Center of Rejuvenation
Aging is associated with structural and functional changes in the heart and is a major risk factor in developing cardiovascular disease. Many recent studies have focused on increasing our understanding of the basis of aging at the cellular and molecular levels in various tissues, including the heart. It is known that there is an age-related decline in cellular quality control pathways such as autophagy and mitophagy, which leads to accumulation of potentially harmful cellular components in cardiac myocytes.
A growing body of data support the anti-aging effects of enhanced autophagy. Many studies have demonstrated that enhancing autophagy by limiting caloric intake, genetic manipulation, or pharmacological treatments increases lifespan in various organisms. For instance, transgenic mice with systemic overexpression of Atg5 have enhanced autophagic activity in tissues which leads to health benefits such as reduced weight gain with age and extended life spans compared to wild type mice.
The cardioprotective effects of enhanced autophagy during the aging process were recently confirmed, who developed a Becn1 knock-in mouse model with constitutively increased basal autophagy due to a disruption in the Bcl-2 binding to Becn1. They found that health and life spans are significantly increased in the knock-in mice. Moreover, aged Becn1 knock-in mice have reduced cardiac hypertrophy and interstitial fibrosis compared to aged-matched wild type mice, confirming that preserving autophagy in the heart delays or even prevents cardiac aging.
In summary, declines in autophagy and mitophagy in tissues clearly play a role in the aging process and contribute to development of age-related diseases. The main questions that remain unanswered include: why are autophagy and mitophagy suppressed with age and can these pathways be restored in the aged heart? Relatively little is still known about the molecular mechanism underlying the decrease in autophagy and mitophagy and whether there are tissue specific differences. Although manipulation of autophagy and mitophagy pathways are protective in pre-clinical models, the level of activity must be carefully monitored as excessive autophagy can lead to excessive degradation of key cellular components. Increased knowledge into how these pathways are regulated as well as altered with age will allow for more specific manipulation. Further understanding will also provide important insights into how future therapies can protect the heart against age-specific functional decline.
You seem to be coming to the argument that mitochondrial dysfunction is not actually a primary cause of aging, but is in fact a downstream outcome of primary damage.
@jimofoz: The sort of dysfunction that occurs broadly throughout the body in every cell due to altered mitochondrial dynamics and loss of mitophagy definitely looks downstream of something. It results from epigenetic change and altered protein levels, which has to be a reaction to whatever it is a reaction to.
Stochastic mitochondrial DNA damage in the SENS model, which is a primary cause, isn't expected to do this sort of thing globally, but rather cause a small set of cells to be very dysfunctional.
I have wondered for some time, isn't death from natural causes usually just because the heart stops beating? I mean, it fails as a muscle, loaded up with lipofuscin?