The Role of Mechanoaging in the Deterioration of Intestinal Homeostasis with Age

Advanced age is the leading risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive aging remain largely unknown. Inflammaging—i.e., chronic, sterile, low- grade inflammation during the aging process—has been implicated as crucial to the pathogenesis of age-related frailty and diseases. While the precise etiology and the underlying cellular and molecular processes of inflammaging are not yet fully understood, compromised intestinal epithelial homeostasis and barrier function have been indicated to play a critical role in its development. Studies across various species demonstrated reduced barrier integrity and increased intestinal permeability with age, ultimately leading to microbial and (endo)toxin translocation associated with systemic inflammation. Likewise, enhancing intestinal barrier integrity counteracts aging-associated inflammation and frailty. However, clear gaps remain in our understanding of mechanisms that contribute to the decline in intestinal homeostasis with age. A key feature of aging is the mechanical stiffening of organs, and studies in bone marrow, nervous system, vasculature, skin, and cartilage demonstrated that their stiffening with age is tightly correlated with their functional decline. However, the contribution of intestinal mechanoaging to its dysfunction and inflammaging is unknown. We hypothesize that the aging-associated mechanical stiffening of the intestine contributes to the decline in intestinal epithelial homeostasis and barrier integrity with age. Our hypothesis is supported by recent work from our team and preliminary results showing that stiffening potently disrupts intestinal epithelial homeostasis (including the loss of stem cells) and barrier integrity, which are reminiscent of phenotypes observed in an aged epithelium. Moreover, aging triggers intestinal stiffening and induces the expression of mechanosensitive channel PIEZO1— whereas the attenuation of the mechanosignaling pathway mitigates the aging phenotype. We will test our hypothesis in three Specific Aims: Aim 1 will determine the causal role of the intestinal mechanoaging in the decline in its homeostasis and function with age; Aim 2 will elucidate the role of PIEZO1 in the aging-associated intestinal dysfunction and inflammaging; and Aim 3 will decipher whether the attenuation of mechanosignaling cascade rescues the aging phenotypes in human epithelial cells. Achievement of our objectives will demonstrate that the stiffening of the intestine with age plays a central role in its functional deterioration and inflammaging. It will also highlight mechanosignaling pathway as a viable therapeutic target to decelerate aging-related intestinal dysfunction and promote healthy aging. Project Number: 1R01AG090583-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Nima Saeidi | Institution: MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MA | Award Amount: $629,562 | Activity Code: R01 | Study Section: Cellular Mechanisms in Aging and Development Study Section[CMAD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11227200