Cell and tissue biology always turns out to be more complicated than we would all prefer. Present understanding is rarely complete to the point at which all obstacles are known. It is one of the reasons why the development of new classes of medical therapy is a challenging business. Consider the topic of autophagy in aging, for example. Autophagy is the name given to a collection of processes responsible for recycling unwanted and damaged molecules and structures in the cell. Material is conveyed, in one way or another depending on the type of autophagy, to a lysosome and engulfed. Lysosomes are membrane-bound packages of enzymes capable of breaking down just about anything a cell is likely to encounter.
The efficiency of autophagy declines with age. There is evidence for loss of function in the processes moving materials to a lysosome, and much more evidence for lysosomes themselves to become dysfunctional. Increased autophagy is involved in most of the approaches discovered to date that slow aging via alterations of cellular metabolism. This includes calorie restriction and other forms of mild stress that trigger cells into increased maintenance activities, leading to a net gain in function. Equally, too much autophagy is harmful to cells, and in some tissues it appears that autophagy increases rather than decreases with aging. It may also be becoming less efficient, but challenges arise in the matter of how to measure a complicated system of many component parts that is both more active and less effective. Loss of efficiency may only be visible via some forms of measurement, leading to contradictory reports in the scientific literature.
Pre-clinical and clinical evidence show that caloric restriction (CR) is an effective method to ameliorate cardiovascular pathologic remodeling and to improve cardiovascular function. For example, in a rat model for myocardial infarction and post-ischemic heart failure, 1-year long CR mitigated pathologic left ventricular remodeling and improved cardiac function and inotropic reserve. An average 11% CR for a 2-year period reduced cardiometabolic risk factors and increased predictors of health span and longevity in a healthy human clinical trial.
One of the underlying mechanisms for the anti-aging effect of CR is induction of autophagy, a process that removes senescent cells from tissues and thus prevent spreading of cellular senescence. It is now well established that autophagy is a converging point for the beneficial effects of longevity drugs such as rapamycin, other rapalogs, metformin, and resveratrol.
Optimal levels of autophagy is an evolutionarily-conserved intracellular catabolism process essential to preserve cellular homeostasis in response to the same or similar stressors that induce cellular senescence. Cellular senescence, an important hallmark of aging, is a critical factor that impairs repair and regeneration of damaged cells in cardiovascular tissues. Therefore, therapeutic targeting of autophagy can be an effective approach to mitigate cardiovascular diseases. In particular, cardiomyopathy caused by diabetes involves extensive deregulation of cardiac mitochondrial function and induction of mitochondrial autophagy (mitophagy) that may start as a survival mechanism, but can cause cell death when excessive.
Autophagy encompasses highly regulated cellular processes to maintain cellular homeostasis and proteostasis, and eliminates potentially harmful cellular stressors that induce cell death. The highly-conserved autophagy machinery forms double-membraned autophagosomes to sequester portions of the cytoplasm and organelles, and trafficks these autophagosomes to lysosomes for degradation. Various forms of autophagy including macroautophagy, microautophagy, and chaperone-mediated autophagy all lead to turnover of intracellular components.
While autophagy is a catabolic process that degrades damaged organelles, misfolded proteins, and other harmful stressors, it also generates new building blocks (for example amino acids), energy for anabolism in conditions of nutrient deprivation, and promotes self-renewal and differentiation of pluripotent stem cells which is essential for repair of damaged tissue. Autophagy dysregulation tilts the balance from autophagy being the protective mechanism to exerting detrimental effects on cells leading to apoptosis, to whole-organ dysfunction, and organismal demise. Therefore, better understanding of the underlying molecular mechanisms of therapeutic induction of autophagy is of utmost importance, and the levels of autophagy need to be carefully monitored.