Targeting the Aging of the Immune System in the Context of Frailty

The immune system declines into a state of incapacity (immunosenescence) and chronic inflammation (inflammaging) with advancing age. Unresolved inflammatory signaling is disruptive of tissue function in many ways, from reduced stem cell activity to pathologically altered somatic cell behavior. It is thought to be important in the declining muscle mass and strength that contributes to age-related frailty. Thus addressing immune aging is a significant and important target in the treatment of aging as a whole.

Frailty is a highly prevalent geriatric syndrome that has attracted significant attention from physicians and researchers due to its associated increase in vulnerability and healthcare costs, especially in the elderly population. Generally, frail patients suffer from multiple chronic diseases, with comorbidities and polypharmacy greatly challenging their health management. Gerontologists suggest that targeting the common pathogenesis of comorbidities rather than a single disease is probably a better solution for older people. Multiple factors contribute to development of frailty with advancing age, thus the therapeutic target is diversed depends on specific condition. Nutrition supplements and physical exercise are proved to be helpful in preventing and treatment of frailty, however, valid pharmaceutical intervention is scarce.

Mesenchymal stem cells (MSCs) can exert regenerative effects and possess anti-inflammatory properties, offering a promising therapeutic strategy to address the pathophysiologic problems of frail syndrome. Currently, MSC therapy is undergoing phase I and II trials in human subjects to endorse the safety and efficacy of MSCs for aging frailty.

Numerous studies have shown that rapamycin and rapalogs, considered novel and promising longevity agents, can extend lifespan. Interestingly, these agents showed an immunosuppressive effect at high doses and an immune stimulatory effect at low doses. However, the reason for these immunity-boosting effects is unclear. The inhibition of mammalian target of rapamycin (mTORC1) is a possible explanation, as mTOR can regulate the STAT signaling pathway. A study showed a significant difference in STAT phosphorylation levels in the T cells of healthy people compared with unhealthy senescent people.

Senolytics are a novel type of agent. The interference of stem cell signaling pathways temporarily disables senescent cell anti-apoptotic pathway (SCAP), thus targeting selectively senescent cells. In addition to its main effect on clearing senescent cells, senolytics can also eliminate pro-inflammatory cytokines. According to the study, inflammation symptoms are relieved after the administration of senolytics. A recent study found reduced SASP and coronavirus-related mortality in old mice after the administration of senolytics.

A low level of nicotinamide adenine dinucleotide (NAD)+ is reportedly associated with the poor function of mitochondria and metabolic reprogramming of immune cells; therefore, NAD+ is also recognized as a therapeutic target for aging immunity. Promising data has demonstrated that administrating nicotinamide mononucleotide, the NAD+ precursor, into mice could maintain NAD+ levels and mitochondrial function, with the mitochondrial function of immunocytes being essential for controlling virus propagation.

A centenarian study revealed that longevity is associated with gut microbial structures, making individuals more potent against age-associated disorders and leading to a longer life. The microbiota-targeting probiotic and dietary interventions affect natural aging by enhancing oxidation resistance, regulating metabolism, suppressing chronic inflammation, and promoting immune homeostasis. Immunosenescence may have a certain influence on human microbial composition, function, and diversity. In addition, fecal microbiota transplantation or prebiotic/probiotic/synbiotic supplementation in the diet is beneficial for restoring active microbiota and extending a healthy lifespan. Thus, there are multiple ongoing developments in this field to ease the process of aging and reduce the risk of potential disabilities that could lead to a significant decrease in the quality of life of elderly individuals.