Autophagy is Everywhere in Aging
Researchers who work on autophagy might well feel justified in issuing the claim that the processes of autophagy are involved in near every aspect of aging. Autophagy is cellular housekeeping, the recycling of damaged or unwanted structures and molecules inside the cell. In chaperone-mediated autophagy, very selective chaperone proteins pick up other molecules and carry them to lysosomes. In macroautophagy, materials to be broken down are engulfed in an autophagosome, which then travels to the lysosome and fuses with it. In microautophagy, the lysosome engulfs materials directly. In all cases, the lysosome is the end of the journey, where a mix of enzymes will slice up the waste material into parts suitable for reuse. The result of smoothly running autophagy is a cell that is less cluttered with damaged parts and waste, and thus a cell that causes fewer issues to the tissue it is a part of.
This business of keeping molecular wear and tear inside cells to a minimal level appears a noteworthy determinant of aging. Many of the methods shown to slow aging in laboratory species such as flies, nematodes, and mice involve increased autophagy. Cells react to stress by increasing autophagy, largely regardless of the type of stress. This is one of the reasons why short and mild exposure to stress improves health, the process known as hormesis. Radiation, lack of nutrients, heat, cold ... it all can lead to improved long-term health and lengthened life span. Autophagy is an important part of this outcome, and in some cases it is a necessary part: animals with disabled autophagy do not gain the benefits to health and longevity provided by calorie restriction, for example.
In the open access paper here, the authors walk through the Hallmarks of Aging, linking them to autophagy. While, yes, one can link autophagy to near everything in aging, and particularly given that autophagy declines with age, it is important to remember that there is a limited upside to increased autophagy as a therapeutic approach. The rough location of that limit is illustrated by calorie restriction; one can imagine a therapy that does twice as well as calorie restriction at upregulating autophagy, but that isn't going to add decades to the human life span. In fact stress responses in our species have only small effects on life span in comparison to those observed in mice. Calorie restriction may increase maximum life span by 40% in mice, but it certainly doesn't do that in our species. Five years of additional life expectancy would be about the upper limit of what we might expect - though the health benefits along the way are certainly well worth having.
Hallmarks of Aging: An Autophagic Perspective
Loss of Proteostasis
Proteostasis is one of the major functions of autophagy in normal tissues. Imbalance of proteostasis due to aging leads to protein aggregation, accumulation of misfolded proteins and in the end to cellular dysfunction, among others. Notably, carbonylation due to oxidative stress is one of the changes that leads to loss of proteostasis. To avoid cell death or dysfunction, numerous homeostatic mechanisms turn on, mainly autophagy and the Ubiquitin-Proteasome-System (UPS). Because autophagy is considered one of the most important intracellular homeostatic processes, an alteration or deterioration of this pathway could modify the normal cell functioning, including a variety of diseases and normal cell physiology declination.
Mitophagy is a basal process involved in the autophagic degradation of mitochondria. It is necessary in normal differentiation of certain cell types such as red blood cells, in embryogenesis, immune response, cell programming, and cell death. Mitophagy is required not only to remove damaged mitochondria, but also to promote the biosynthesis of new ones, supporting the mitochondrial quality control. Given that mitochondria are implicated in bioenergetics and ROS production, the mitophagy plays an important role in cell homeostasis. Additionally, a decrease in mitophagy is observed in aged animals and this contributes to aging phenotypes.
Deregulated Nutrient Sensing
Because autophagy is a catabolic mechanism, it can be assumed to be implicated in cellular and systemic metabolism. Metabolic stress responses could be compromised due to a decline in autophagic activity. As an important process regulating the general cellular status, autophagy can also link metabolic pathways to maintain homeostasis under a variety of conditions. In this sense, it has been demonstrated that, after nutrient or growth factor deprivation, ULK1 and ULK2 are activated, and these kinases phosphorylate and activate several glycolytic enzymes as well as autophagic proteins. This makes it possible to obtain metabolites thanks to glucose uptake, gluconeogenic pathway blockage, and autophagic degradation of cytosolic components. Supporting this, mTOR hyperactivation was found in several diseases such as obesity, metabolic syndrome, and type 2 diabetes, which highlights the importance of a tight regulation of autophagy as well as the nutrient sensing pathway.
In the last decade, several studies have demonstrated that autophagy or autophagic-related molecules act as a "safeguard" of genome stability both directly (DNA repair modulation) and indirectly (by acting as a homeostatic response). Several mouse models have provided substantial information regarding genomic instability and its connection with healthy and pathological aging.
Taken together, organismal models as well as in vitro studies highlight the importance of epigenetics throughout life. The relationship between epigenetic changes and autophagy needs to be deeply studied in order to understand the regulatory loop that seems to be involved in development and aging.
Telomerase activity can support cell cycle progression by preventing the arrest due to short telomeres, leading to a putative malignancy. Remarkably, overexpression of Beclin1 in HeLa cells revealed that telomerase activity is reduced after autophagy induction. This approach argues in favor of the hypothesis that autophagy plays an important tumor suppressor role by the modulation of telomerase activity in somatic cells. This autophagic response arises in order to avoid genome instability and telomeric dysfunction, thus promoting cell survival.
Autophagy regulates the senescence of vascular smooth muscle cells. Intriguingly, autophagy can mediate the transition to a senescent phenotype in oncogene-induced senescence fibroblasts, making possible the protein remodeling needed to establish the senescent phenotype under oncogene activation. It is proposed that type of autophagy, the exact moment when it acts, and the place where it occurs can define the pro or anti-senescence role of autophagy.
Stem Cell Exhaustion
Self-renewal is important to maintain the population of tissue-specific stem cells throughout life. Importantly, as we age, stem-cell activity decreases. It has been shown that autophagy is necessary for preservation and quiescence of hematopoietic stem cells (HSCs). Autophagy is also important to maintain stemness in bone marrow-derived mesenchymal stem cells. In addition, Atg7 loss in aged muscle stem cells (satellite cells) of transgenic mice caused altered mitophagy and an accumulation of ROS, all features of senescence that diminish the regenerative potential of aged satellite cells.
Its a piece of the puzzle. Plus for some people with genetics or ailments reducing autophagy they could potentially get substantial benefit from upregulating autophagy to youthful levels.
As a goal we should have bio-markers that measure the autophagy activity in the person. And then if they are low like in obese people with type II diabetes, drugs that upregulate autophagy to healthy levels.
Meanwhile another person who has good autophagy genetics, exercises a lot, restricts calories, that person wouldn't need to take those drugs, at least until a later age.
Since autophagy can't handle lipofuscin, can apoptosis get rid of it? As in, the whole cell dies and gets eaten by phages or flushed into the lymph system?
Reply to Chris Zell.
Already in 1967 it was published in a major nutrition journal that "lipofuscin was formed in proportion to the amount of polyunsaturated fat and oxidants in the diet"
Hence if we cannot remove lipofuscin we can limit their buildup by reducing intake of easily oxidated PUFAs, specifically omega-6 since it is also deemed inflammatory compared to omega-3 with the opposite characteristics.
Avoiding all cheap vegetable oils, in particular food deep fried in such oils as the oil remaining on the food already has been heated and therefore partly oxidised even before eaten.
But who wants easily oxidised fats in tissues when they can break down if we are exposed to stresses and our body's antioxidant usage exceeds its intake? Using any such fats looks like an open invitation to all kinds of degenerative disease. And when saturated fats, the most stable of all fats, now proven to not have a role in heart disease as proposed and accepted without due diligence in the 1960's, the required swap is obvious.
If you find any way to get rid of already formed lipofuscin, please let me know. I have seen that my brown spots have reduced in size and colour since I stopped omega-6 intake about 10 years ago, but it is subjective. Maybe the autophagy process is just short of specific enzymes to enable it to break down lipofuscin?