Aging and age-related diseases: from mechanisms to therapeutic strategies

Abstract

Aging is a physiological process mediated by numerous biological and genetic pathways, which are directly linked to lifespan and are a driving force for all age-related diseases. Human life expectancy has greatly increased in the past few decades, but this has not been accompanied by a similar increase in their healthspan. At present, research on aging biology has focused on elucidating the biochemical and genetic pathways that contribute to aging over time. Several aging mechanisms have been identified, primarily including genomic instability, telomere shortening, and cellular senescence. Aging is a driving factor of various age-related diseases, including neurodegenerative diseases, cardiovascular diseases, cancer, immune system disorders, and musculoskeletal disorders. Efforts to find drugs that improve the healthspan by targeting the pathogenesis of aging have now become a hot topic in this field. In the present review, the status of aging research and the development of potential drugs for aging-related diseases, such as metformin, rapamycin, resveratrol, senolytics, as well as caloric restriction, are summarized. The feasibility, side effects, and future potential of these treatments are also discussed, which will provide a basis to develop novel anti-aging therapeutics for improving the healthspan and preventing aging-related diseases.

Keywords: Age‐related diseases; Aging; Anti‐aging drugs; Hallmarks of aging.

Fig. 1

Metformin targets the major pathways of aging. Extracellularly, metformin decreases insulin levels and IGF-1 signaling while influencing multiple cytokines to participate in anti-aging processes. Intracellularly, metformin reduces ROS production by inhibiting mitochondrial complex I in the electron transport chain generation and AMPK activation, simultaneous increase in mTOR signal inhibition and SIRT1 activation, which resulting in a longer life-span; Metformin affects inflammatory responses, cellular stress responses and autophagy responses, etc. by acting both inside and outside the cell. These cellular processes are the primary biological responses associated with aging

Fig. 2

Rapamycin regulates lifespan primarily through the mTOR signaling pathway. mTOR exists mainly in two functionally distinct complexes termed mTORC1 and mTORC2. Rapamycin inhibits mTORC1 on an intermittent basis, while long-term administration also inhibits mTORC2 in most tissues. Inhibition of mTORC1 promotes protein and nucleotide synthesis as well as autophagy responses, while also reducing cellular stress responses. These effects of rapamycin may promote longevity. In contrast, inhibition of mTORC2 leads to metabolic dysfunction and reduced lifespan, but the exact mechanism is unclear

Fig. 3

Resveratrol is involved in anti-aging as an activator of the sirtuin family and the Nrf2 pathway. Inhibition of mitochondrial ATP production by resveratrol leads to activation of AMPK, which enhances NAD + availability thereby overcoming the rate limitation imposed by this cofactor on SIRT1 enzyme activity. In turn, resveratrol directly activates SIRT1 thereby positively controlling AMPK activity. Together, AMPK and SIRT1 form a positive feedback pathway to prolong life by modulating multiple downstream factors. In addition, resveratrol can act directly on transcriptional regulators thus acting as an anti-inflammatory and antioxidant effect

Fig. 4

Senolytic therapies target aging. During the aging process, senescent cells accumulate in large amounts in tissues and are associated with the development of various age-related diseases. Senolytics can help slow down the aging process by eliminating the accumulation of senescent cells, reducing age-related diseases and prolonging healthspan. Uncontrolled activation of SASP can cause chronic inflammation, leading to tissue dysfunction, this ultimately leads to aging and age-related diseases. Senolytics also can positively impact aging-related diseases by modulating the regulatory network of SASP in senescent cells and by inhibiting SASP from exerting its deleterious effects