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Senescent Cells Drive Frailty through Systemic Signals

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Abstract

Senescent cells drive ageing and the associated loss in health and lifespan. Whether this is mediated by systemic signalling remained unclear. Recently, Xu et al. [1] (Nat. Med. 2018;24:1246–1256) answered this question by injecting senescent cells into young mice and observing a long-lasting increase in frailty and mortality.

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... Ageing is a natural, progressive and irreversible process characterized by morphological, psychological, functional, biochemical and nutritional changes (World Report on Ageing And Health, 2015). Physical inactivity (PI) is a factor that contributes to the starting of mass and muscle function decline in the elderly often related to sarcopenia and physical frailty (Lehmann, Baar, & de Keizer, 2018). Combined to protein nutritional intervention, exercise appears as an effective way to prevent muscle mass and physical fitness decline (Hernández Morante, Martínez, & Morillas-Ruiz, 2019). ...
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Background: Ageing is a natural, progressive and irreversible process characterized by morphological, psychological, functional, biochemical and nutritional changes. Physical inactivity (PI) is a factor that contributes to the starting of mass and muscle function decline in the elderly, often related to sarcopenia and physical frailty. Combined to protein nutritional intervention, exercise appears as an effective way to prevent muscle mass and physical fitness decline. In addition, the elderly population has difficulty in maintaining adequate protein nutrition and are the least involved in systematic exercise programs. This exploratory study was conducted to understand the isolated and combined effects of a 16-weeks of branched chain aminoacids (BCAA) supplementation (BS) and muscle strength exercise program (MSE) on functional-fitness performance in octogenarians. Methods: The sample consisted of 18 participants aged 82.97±8.05 years old, institutionalized in social care centres. They were divided into two groups: group 1 (MSE+BS, n=10); group 2 (BS, n= 8). Group 1 performed an elastic band strength exercise program carried out during 16-weeks together with BCAA supplementation consisting of ingesting 0.21g/kg/day of unflavoured powder diluted into 200mls of water, immediately after exercise. Group 1 did only the BCAA supplementation. To evaluate the functional capacity of the elderly, the short battery of tests SPPB was used in the initial and final intervention evaluation. Results: After 16 weeks, group 1 (MSE+BS) showed a significant increase in all the SPPB tests performance, particularly in the test consisting in rising from a chair and seating down for 5 times. The SB group showed only a short decrease in the time taken to perform the 3 meters walk test (p < .05). Conclusion: Our study revealed that exercise plus supplementation with BCAAs was able to improve physical fitness function, while BCAA supplementation alone had limited effects. Satisfactory results in physical function could be explained by the added effects of exercise and BCAA supplementation on the protein synthesis effect.
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Frailty is a clinical geriatric syndrome characterized by decreased multisystem function and increased vulnerability to adverse outcomes. Although numerous studies have been conducted on frailty, the underlying mechanisms and management strategies remain unclear. As rodents share homology with humans, they are used extensively as animal models to study human diseases. Rodent frailty models can be classified broadly into the genetic modification and non-genetic modification models, the latter of which include frailty assessment models (based on the Fried frailty phenotype and frailty index methods) and induced frailty models. Such models were developed for use in investigating frailty-related physiological changes at the gene, cellular, molecular, and system levels, including the organ system level. Furthermore, exercise, diet, and medication interventions, in addition to their combinations, could improve frailty status in rodents. Rodent frailty models provide novel and effective tools for frailty research. In the present paper, we review research progress in rodent frailty models, mechanisms, and management, which could facilitate and guide further clinical research on frailty in older adults.
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Cellular senescence is the permanent arrest of cell cycle, physiologically related to aging and aging-associated diseases. Senescence is also recognized as a mechanism for limiting the regenerative potential of stem cells and to protect cells from cancer development. The senescence program is realized through autocrine/paracrine pathways based on the activation of a peculiar senescence-associated secretory phenotype (SASP). We show here that conditioned media (CM) of senescent mesenchymal stem cells (MSCs) contain a set of secreted factors that are able to induce a full senescence response in young cells. To delineate a hallmark of stem cells SASP, we have characterized the factors secreted by senescent MSC identifying insulin-like growth factor binding proteins 4 and 7 (IGFBP4 and IGFBP7) as key components needed for triggering senescence in young MSC. The pro-senescent effects of IGFBP4 and IGFBP7 are reversed by single or simultaneous immunodepletion of either proteins from senescent-CM. The blocking of IGFBP4/7 also reduces apoptosis and promotes cell growth, suggesting that they may have a pleiotropic effect on MSC biology. Furthermore, the simultaneous addition of rIGFBP4/7 increased senescence and induced apoptosis in young MSC. Collectively, these results suggest the occurrence of novel-secreted factors regulating MSC cellular senescence of potential importance for regenerative medicine and cancer therapy.
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The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density, and renal function in both fast aging XpdTTD/TTD and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored.
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