Autophagy in the Context of Immune System Aging

Autophagy is the name given to a collection of cellular maintenance processes that identify and break down worn and unwanted proteins and structures in the cell. More efficient autophagy in principle produces better cell and tissue function, and, over the long term, slower aging. A sizable portion of the research community is interested in autophagy in the context of aging, but outside the development of calorie restriction mimetic drugs, few groups are working towards therapies intended to upregulate autophagy in a targeted fashion. A program in the Life Biosciences portfolio is one of the limited number of examples.

The ability of calorie restriction to lengthen healthy life in short-lived species is largely the reason that autophagy became interesting, though many approaches that slow aging in animal studies are characterized by upregulation of autophagy. In the case of calorie restriction, extension of life span depends on the correct operation of autophagy. A good number of studies provide other evidence that points to improved autophagy as the primary cause of health and longevity benefits resulting from a reduced calorie intake.

One of the many benefits produced by calorie restriction, and calorie restriction mimetics capable of upregulating autophagy, is a slowed decline of the immune system in later life. With this in mind, today's open access paper discusses the relationship between autophagy and immune aging. As in other considerations of autophagy, it is plausible that the more important portion of autophagic activity is the removal of worn and damaged mitochondria, the selective autophagy known as mitophagy. Mitochondria decline in effectiveness with age, in large part due to faltering mitophagy. This has detrimental effects throughout the body that include altered behaviors and capabilities of immune cells.

Autophagy takes it all - autophagy inducers target immune aging

Recently, a plethora of studies revealed that selective autophagy, in close association with immunometabolism, is key in modulating immunity and immune cell dynamics. In addition, autophagy is further involved in differentiation and proliferation of immune cells, although what exactly underlies molecular mechanisms remains partly elusive. Mounting evidence indicates that mitophagy, which encompasses selective degradation of damaged or excessive mitochondria, is an especially crucial regulator of innate immune cell function. Autophagy also prevents mitochondrial DNA escaping into the cytoplasm by maintaining mitochondrial homeostasis, which inhibits initiation of type I interferon signalling and, ultimately, inflammation. Furthermore, autophagy is essential for T cell immunity and its decline with age leads to immunosenescence.

During the last two decades, several trailblazing studies have suggested that innate and adaptive immunity are key to fight not only infectious diseases but also non-communicable diseases including typical age-related conditions, such as cancer. Considering that autophagy facilitates adaptive immune cell activation and differentiation, and partially reverses systemic immunosenescence via modulating T cell immunity, clinical implementation of autophagy inducers provides high therapeutic potential.

Drug discovery has identified numerous small compounds that can reverse age-associated effects via autophagy. These have been suggested to extend median and maximal lifespan, underpinned by in vivo and in vitro data obtained in various animal models. Importantly, lifestyle and nutrition, particularly exercise and dietary restriction enhance the autophagy pathway. Several repurposed and already FDA-approved drugs that either inhibit mTORC1 or activate AMPK have recently gained considerable attention as promising immunoprotective interventions that could be translated into clinic within the next decade. Here, we focus on the three most-promising drugs (rapamycin, metformin, and spermadine) and on dietary restriction as a lifestyle change.

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