Abstract
The biguanide metformin is the first drug to be tested as a gerotherapeutic in the clinical trial TAME (Targeting Aging with Metformin). The current consensus is that metformin exerts indirect pleiotropy on core metabolic hallmarks of aging, such as the insulin/insulin-like growth factor 1 and AMP-activated protein kinase/mammalian Target Of Rapamycin signaling pathways, downstream of its primary inhibitory effect on mitochondrial respiratory complex I. Alternatively, but not mutually exclusive, metformin can exert regulatory effects on components of the biologic machinery of aging itself such as chromatin-modifying enzymes. An integrative metabolo-epigenetic outlook supports a new model whereby metformin operates as a guardian of cell identity, capable of retarding cellular aging by preventing the loss of the information-theoretic nature of the epigenome. The ultimate anti-aging mechanism of metformin might involve the global preservation of the epigenome architecture, thereby ensuring cell fate commitment and phenotypic outcomes despite the challenging effects of aging noise. Metformin might therefore inspire the development of new gerotherapeutics capable of preserving the epigenome architecture for cell identity. Such gerotherapeutics should replicate the ability of metformin to halt the erosion of the epigenetic landscape, mitigate the loss of cell fate commitment, delay stochastic/environmental DNA methylation drifts, and alleviate cellular senescence. Yet, it remains a challenge to confirm if regulatory changes in higher-order genomic organizers can connect the capacity of metformin to dynamically regulate the three-dimensional nature of epigenetic landscapes with the 4th dimension, the aging time.
Highlights
MetforminThe stochastic and dynamic nature of chromatin structure and epigenetic information allows cells to reach and maintain a differentiated state
There is increasing awareness that non-genetic, environmental, and metabolic stimuli can modify the structure and function of chromatin as a cause of aging [1,2,3,4,5,6]
The current consensus is that metformin exerts indirect pleiotropy on core metabolic hallmarks of aging, such as the insulin/insulin-like growth factor 1(IGF-1) and AMP-activated protein kinase (AMPK)/mammalian Target Of Rapamycin signaling pathways, downstream of its primary inhibitory effects on mitochondrial respiratory complex I [20,21] (Figure 1A)
Summary
Aging is reflected by specific DNA methylation changes; almost one third of the CpG (cytosine-guanine dinucleotide) sites show age-associated DNA methylation alterations, of which 60% become hypomethylated and 40% hypermethylated upon aging [165]. Cell-intrinsic manipulations such as partial reprogramming using short-term cyclic expression of the so-called “Yamanaka factors” (Oct, Sox, Klf, and c-Myc) resets DNA methylation epigenetic clocks and ameliorates cellular and physiological hallmarks of aging while maintaining cell identity [7,8,172]. Metformin might operate as a cell-extrinsic manipulator capable of ameliorating age-associated phenotypes by epigenetic remodeling. Given that chronic senescence-associated inflammatory signaling locks cells in highly plastic epigenetic states disabled for reparative differentiation, the anti-senescence activity of metformin might operate as a non-cell autonomous mechanism capable of “unlocking” the aberrant epigenetic plasticity of SASP-damaged aging tissues while simultaneously stimulating differentiation of stem cell-like states to successfully achieve tissue repair or rejuvenation [11]
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