Senescent cells accumulate with age and cause harm via their inflammatory signaling, contributing to the chronic inflammation of aging that is disruptive to tissue structure and function throughout the body. One faction of the research and development community wants to selectively destroy senescent cells via the use of a wide variety of senolytic therapies presently under development. Another faction wants to instead find ways to suppress the inflammatory signaling of these cells. Here find an example of this second area of research, a search for targets that can be manipulated to reduce harmful signaling generated by senescent cells, but which will produce minimal side-effects in non-senescent cells.
In this review, we summarize the current research progress on non-histone high mobility group proteins (HMGs) in the field of aging, particularly their structural characteristics and functional roles in regulating the aging process. As chromatin architectural regulators, HMGs, in collaboration with histones, exert critical influence on chromatin dynamics and gene expression. By competitively binding to specific DNA sites, HMGs alter chromatin accessibility and regulate gene activity, thereby exerting profound effects at various stages of cellular senescence. This regulation involves a wide array of mechanisms and pathways, with a particularly notable impact on the senescence-associated secretory phenotype (SASP) and senescence-associated heterochromatin foci (SAHF).
HMG proteins, particularly members of the HMGA and HMGB families, play pivotal roles in the formation and regulation of SASP and SAHF. SASP comprises pro-inflammatory factors and proteins secreted during cellular senescence, which not only drive the aging process but are also closely associated with various age-related diseases, including chronic inflammation, cardiovascular diseases, and cancer. HMGA proteins promote or inhibit the spread of inflammatory signals by affecting chromatin structure and regulating the expression of SASP-related genes. Meanwhile, HMGB proteins, acting as damage-associated molecular patterns (DAMPs), activate inflammatory pathways and exacerbate the release of SASP. SAHF, as highly compacted heterochromatin regions, silence genes related to proliferation and the cell cycle, marking cells’ entry into a state of permanent cell cycle arrest. The dynamic regulation of HMG proteins is crucial for the formation and maintenance of SAHF.
Recent studies have shown that targeting and blocking HMG proteins, particularly HMGB1 and HMGA2, not only reduces the release of SASP but also effectively inhibits inflammatory responses, thereby slowing the progression of age-related diseases. By inhibiting the extracellular release of HMGB1, researchers have found that sterile inflammation and tissue damage can be alleviated, protecting cardiovascular health and delaying the development of age-related cardiovascular diseases. Targeting these proteins has become a key direction in aging research. Compared to traditional therapies, targeting HMG proteins offers a more precise means of modulating age-related pathophysiological processes with fewer effects on normal cells.
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