Age-Related Dysfunction in Cellular Metabolism Substantially Impacts the Immune System

Most of what to my eyes are less promising lines of research into the treatment of aging are focused on manipulation of cellular metabolism. These approaches, such as targeting the mTOR pathway, largely derive from the study of calorie restriction and the cellular response to stress that is brought on by lack of nutrients. Calorie restriction extends average and maximum life span considerably in short-lived species, up to 40% in mice, for example. It increases the efficiency of cellular maintenance processes and makes cells more frugal in other ways. The impact of aging is slowed, as molecular damage accumulates less rapidly. Yet in long-lived species such as our own, short-term benefits are evident, but the practice of calorie restriction doesn't change human life span by a large amount.

It is thought by some in the research community that many of the changes that take place in short-lived mammals in response to nutrient stress have already evolved to operate consistently in long-lived mammals such as ourselves, precisely in order to make us long-lived. Calorie restriction produces such sweeping changes in the operation of cellular metabolism that researchers make only slow progress towards picking out the areas of importance, or towards expanding the catalog of interactions between pathways and mechanisms and aging.

Cellular metabolism becomes more dysfunctional with age in ways that can be assessed. As today's open access paper notes, some of these changes appear to cause further dysfunction in the immune system. Thus attempting to compensate for age-related metabolic issues by intervening in the mTOR pathway can improve immune function in old people to some degree, and it is believed that similar results can be obtained via other metabolic adjustment. It is worth noting that this is also true of exercise or the practice of calorie restriction! How and why does this improvement in immune function happen? The connections are complicated and still comparatively poorly explored.

Moving away from manipulation of metabolism towards the more direct approach of damage repair, one can improve metabolism by removing lingering senescent cells, a form of tissue damage. The presence of senescent cells disrupts cellular metabolism via the senescence-associated secretory phenotype, signaling that changes surrounding cell behavior for the worse. Removing damage that causes detrimental metabolic change seems a more promising approach than adjusting factors inside cells to try to minimize their response to that damage. Indeed, senescent cell clearance compares very favorably to mTOR inhibition in animal studies.

Targeting Aging: Lessons Learned From Immunometabolism and Cellular Senescence

Two hallmarks of aging, mitochondrial dysfunction and dysregulated nutrient sensing, are tightly associated with metabolic alterations. Increasing research is investigating the role of metabolism in controlling longevity. Three metabolic and nutrient sensing pathways, mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and sirtuins, are under investigation as potential targets for aging.

Although all systems are affected, the hallmarks of aging substantially impact the immune system. It is well known that aging leads to progressive declines in innate and adaptive immunity. This immunosenescence is accompanied by chronic low-grade inflammation, or inflammaging. This results in increased susceptibility to infections, reduced response to vaccination, and increased prevalence of cancers, autoimmune and chronic diseases. Not surprisingly, given that deregulated nutrient sensing and mitochondrial dysfunction are hallmarks of aging, markers of inflammaging also coincide with markers of metabolic dysfunction.

Recent research has highlighted the importance of mitochondrial function and cellular metabolism in controlling immune cell function. Indeed, immunometabolism is critical for proper immune function. What remains to be fully explored is how age and age-associated factors, such as senescent cell accumulation, impact immunometabolism and therefore immune function. This research gap represents a potentially fruitful target for immune modulation in older adults.

Interventions that target dysregulated metabolism or senescence may prove fruitful for improving aged immune responses, leading to additional protection when dealing with infection. In fact, it has been demonstrated that low dose TORC1 inhibition in older adults decreased risk of all infections, upregulated antiviral immunity, and improved influenza vaccination responses. Although further research is necessary to fully elucidate the mechanisms by which metabolic changes with aging contribute to T cell dysfunction, current metabolic therapeutics may prove beneficial for targeting the aging immune system.

Furthermore, targeting senescent cells may also improve immunometabolism with aging. Senolytics, drugs that target senescent cells, have shown great promise with treating age-related diseases and phenotypes. With age, there is increased insulin resistance driven by dysfunction in adipose tissue. Senescent adipocyte progenitor cells were found to be the root cause of dysfunction and when cleared with senolytic treatment, insulin resistance is reversed. Interestingly, many immune cells (including T cells, B cells, and NKT cells), are thought to exacerbate insulin resistance. Taken together, the ablation of the senescence-associated secretory phenotype using senolytics could possibly reverse the deleterious activity of these immune cells which could be beneficial beyond insulin resistance. Furthermore, senolytics may reduce CD38 expressing macrophages and preserve NAD+ levels with aging, offering a promising strategy to enhance metabolic fitness with age.