In the paper I'll point out today, the topic is autophagy and stem cell aging. You can't wander far in the libraries of research relating to aging without bumping into a discussion of autophagy. This is a collection of quality control processes for cellular structures and proteins, working to destroy those that have become damaged or dysfunctional in some way. Damage of any number of different types occurs constantly inside cells, and so does repair: any sort of of unwanted modification of a protein alters its behavior, making it unsuitable for its intended task. Unfortunately, proteins are fragile, and cells are full of reactive molecules and damaging reactions. The longer that damaged components remain in circulation, the more secondary harm they can produce, both within the cell, and beyond in the surrounding tissue. Given that, it is understandable that greater levels of autophagy should produce better function and longer-lasting biological structures at all levels. Indeed, more autophagy slows the aging process to some degree, as demonstrated in numerous studies of short-lived laboratory species. Aging is caused by an accumulation of certain forms of damage that arise from the normal operation of cellular metabolism, and thus processes relating to general damage control tend to have some impact.
Still, there are limits. Greatly increased autophagy only somewhat slows aging. The forms of damage that are important in the long term are not greatly hampered by the constant efforts to repair the far more numerous other forms of damage. It makes sense to consider that aging could really only result from forms of damage that autophagy isn't all that effective at preventing. Consider mitochondrial damage for example, well-studied in the context of aging: the processes of mitophagy break down dysfunctional mitochondria, but the specific mitochondrial damage that causes aging is resistant to mitophagy. The quality control mechanisms cannot efficiently recognize that specific damage and its consequent mitochondrial dysfunction as a signal to remove the problem structures.
Autophagy declines with age, just like every other cellular system, as the components required for recycling of structures become dysfunctional over time. To pick one example, the lysosomes in long-lived cells, responsible for breaking down proteins and other structures in the cell, become bloated by metabolic waste that is hard for them to deal with. This prevents them from carrying out their recycling tasks, and as a result the cell eventually breaks down in a garbage catastrophe. Aging itself might be thought of as a process that commences with a failure of repair: once the maintenance systems decline, everything else follows rapidly. As is the case for autophagy, the tissue maintenance activities of stem cells decline with age, and there are links between the failure of a cellular process and the failure of an entire cell population to carry out its duties.
Proteostasis is necessary for most cellular functions, such as genetic replication, catalysis of metabolic reactions, and the immune response. Impairments in proteostasis can lead to toxic aggregations and accumulation of unwanted proteins resulting in cellular dysfunction. The maintenance of tissue homeostasis and the regenerative capacity after an injury depends on tissue-specific stem cells. The elucidation of the hallmarks of aging identified the impairment of protein homeostasis and stem cell exhaustion as major processes involved in the decline of the regenerative potential capacity linked to the accumulation of age-associated damage.
Autophagy is a highly conserved catabolic process, essential for this protein quality control, where intracellular components are delivered to lysosomes for self-degradation. There are three different types of autophagy depending on the signals that induce the pathway, and the mechanism by which the cargo reaches the lysosome: macro-autophagy (MA), micro-autophagy, and chaperone-mediated autophagy (CMA). In particular, MA is involved in recycling long-lived proteins and cytoplasmic organelles. This process implies the incorporation of proteins, organelles, and cytoplasm in a structure called the autophagosome, which once formed fuses with the lysosome to form autolysosomes and then releasing its content in the lysosomal lumen where it is degraded via acid hydrolases. Autophagy basal levels are very low under normal conditions, and they are activated in response to stress and extracellular cues.
Aging results from the accumulation of cellular damage promoted by chronic stresses of small magnitude. Therefore, being a sensor of stress, autophagy has been linked to aging. Several studies have described a decline in autophagy activity as well as expression of autophagy genes such as Atg1, Atg5, Atg6, Atg7, Atg8, and Atg12 in response to aging in several animal models and human tissues. The majority of these works have focused on MA, the most studied form of autophagic process, but there have also been studies showing a decline in CMA, particularly in the liver and the central nervous system, which have been linked to decreased function in these organs. Longevity studies with gain and loss of autophagy genes in animal models such as yeast, C. elegans, Drosophila and mice, support a direct role for autophagy in longevity, aging and development of age-associated pathologies. This has encouraged the scientific community to identify the precise role and molecular mechanisms of autophagy in aging, as targeting autophagy could be a novel therapy against aging and age-related diseases.
How autophagy decreases with age remains unclear and under intense investigation. Recent works carried on aged muscle stem cells (MSC) and hematopoietic stem cells (HSC) have revealed the impairment of MA in stem cell activity with aging. Moreover, these studies have confirmed that correct functioning of MA is necessary to maintain the appropriate blood system and muscle development and to allow adult stem cell to survive under metabolic stress. These studies suggest that MSC and HSC lose their regenerative abilities when they reach an advanced age and that autophagy is deficient in the old stem cell population. In a recent work, it was found that approximately 30% of aged HSCs exhibited high autophagy levels, maintaining a low metabolic state and strong long-term regeneration potential similar to young HSCs. However, the remaining population of aged HSCs showed loss of autophagy, which causes activated metabolic state, accelerated myeloid differentiation, and impaired HSCs self-renewal activity and regenerative potential.
These studies confirm that autophagy maintains stemness in MSC and HSCs; however, the maintenance of this feature seems to be different in each niche. Whether these results can be translated to other stem cell niches will be determined in the future. In addition, it will also be important to elucidate whether CMA or micro-autophagy play any role in stem cell aging. In summary, there is a requirement of correct autophagy activity for stem cell function, and the pharmacological restoration of autophagy is postulated as a novel strategy to boost stem cell activity for regenerative medicine and aging.