Dynamic Aging: Channeled Through Microenvironment

Abstract

Aging process is a complicated process that involves deteriorated performance at multiple levels from cellular dysfunction to organ degeneration. For many years research has been focused on how aging changes things within cell. However, new findings suggest that microenvironments, circulating factors or inter-tissue communications could also play important roles in the dynamic progression of aging. These out-of-cell mechanisms pass on the signals from the damaged aging cells to other healthy cells or tissues to promote systematic aging phenotypes. This review discusses the mechanisms of how senescence and their secretome, NAD⁺ metabolism or circulating factors change microenvironments to regulate systematic aging, as well as the potential therapeutic strategies based on these findings for anti-aging interventions.

Keywords: NAD+; SASP; aging; intercellular communication; microenvironment.

FIGURE 1

Senescence-associated secretory phenotype and tissue homeostasis. Senescence is triggered by telomere attrition, oncogene activation and radiation or chemotherapy treatment. Senescent cells can be characterized by a series of features including morphological changes, increased β-galactosidase activity, chromatin remodeling, metabolic reprogramming, secretion of SASP factors and molecular biomarkers like p16^Ink4a, p21, etc. Influence of SASP in tissue homeostasis is context dependent: in short term, SASP factors involve DDR signaling pathways, wound healing and embryogenesis to help maintain tissue homeostasis; in long term, SASP factors promote immunosenescence in aging-relative diseases such as neurodegenerative diseases, idiopathic pulmonary fibrosis, cardiovascular disease, liver fibrosis and cirrhosis, sarcopenia and skin aging. DDR, DNA damage response.

FIGURE 2

Senescent cell types and the SASP factors they secret in different tissues. In different tissues, various senescent cells secrete classic or specific SASP factors in autocrine and paracrine ways. Some signaling molecules such as NO which accordingly change to elevate chronic inflammation, induce tissue dysfunction and accelerate aging. VSMCs, vascular smooth muscle cells. LSECs, liver sinusoidal endothelial cells; HSCs, hepatic stellate cells.