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Preclinical rodent models are essential research tools for improving understanding of physiological aging processes in humans. However, the translatability of findings obtained leveraging rodent models to humans is limited, likely due in part to differences in macronutrient composition of the diets. Here, we investigated the impact of a 3-month diet intervention in old male C57BL/6JN mice in which the macronutrient composition was aligned with that of a midlife/older adult in the United States, compared to a traditional rodent diet, and assessed various phenotypes that are typically altered with aging. Following the diet period, mice fed the human macronutrient-matched diet had greater quadricep and subcutaneous adipose and visceral adipose tissue masses compared to animals fed a traditional mouse diet. Frailty, assessed using a clinical frailty index, was lower, while grip strength was higher in mice fed the human-matched diet. Circulating metabolite and inflammatory cytokine profiles were altered in mice fed the human-matched diet. Notably, mortality rate (assessed in animals who died or were euthanized per veterinary recommendation before the pre-determined end of study euthanasia), tended to be lower in mice fed the human-matched diet. The present study underscores the importance of diet in rodent studies of aging, as differences in macronutrient composition can affect various physiological processes in old mice that are relevant to aging research., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

The arterial system is integral to the proper function of all other organs and tissues. Arterial function is impaired with aging, and arterial dysfunction contributes to the development of numerous age-related diseases, including cardiovascular diseases. The gut microbiome has emerged as an important regulator of both normal host physiological function and impairments in function with aging. The purpose of this review is to summarize more recently published literature demonstrating the role of the gut microbiome in supporting normal arterial development and function and in modulating arterial dysfunction with aging in the absence of overt disease. The gut microbiome can be altered due to a variety of exposures, including physiological aging processes. We explore mechanisms by which the gut microbiome may contribute to age-related arterial dysfunction, with a focus on changes in various gut microbiome-related compounds in circulation. In addition, we discuss how modulating circulating levels of these compounds may be a viable therapeutic approach for improving artery function with aging. Finally, we identify and discuss various experimental considerations and research gaps/areas of future research.

Cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to age-related arterial dysfunction, in part, by promoting oxidative stress and inflammation, which reduce the bioavailability of the vasodilatory molecule nitric oxide (NO). In the present study, we assessed the efficacy of fisetin, a natural compound, as a senolytic to reduce vascular cell senescence and SASP factors and improve arterial function in old mice. We found that fisetin decreased cellular senescence in human endothelial cell culture. In old mice, vascular cell senescence and SASP-related inflammation were lower 1 week after the final dose of oral intermittent (1 week on-2 weeks off-1 weeks on dosing) fisetin supplementation. Old fisetin-supplemented mice had higher endothelial function. Leveraging old p16-3MR mice, a transgenic model allowing genetic clearance of p16 INK4A -positive senescent cells, we found that ex vivo removal of senescent cells from arteries isolated from vehicle- but not fisetin-treated mice increased endothelium-dependent dilation, demonstrating that fisetin improved endothelial function through senolysis. Enhanced endothelial function with fisetin was mediated by increased NO bioavailability and reduced cellular- and mitochondrial-related oxidative stress. Arterial stiffness was lower in fisetin-treated mice. Ex vivo genetic senolysis in aorta rings from p16-3MR mice did not further reduce mechanical wall stiffness in fisetin-treated mice, demonstrating lower arterial stiffness after fisetin was due to senolysis. Lower arterial stiffness with fisetin was accompanied by favorable arterial wall remodeling. The findings from this study identify fisetin as promising therapy for clinical translation to target excess cell senescence to treat age-related arterial dysfunction., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Adverse changes in the gut microbiome with aging are an emerging mediator of arterial dysfunction, which contributes to cardiovascular disease (CVD) development. We investigated the therapeutic potential of enhancing the bioavailability of gut-derived short-chain fatty acids (SCFAs; produced from dietary fiber) for improving age-related arterial dysfunction. We performed gut microbial whole-genome sequencing in young (3 months) versus old (24 months) male C57BL/6N mice to explore changes in bacterial taxonomic abundance and functional pathways with aging and relations to arterial function. We then supplemented young and old mice with the SCFA acetate in drinking water versus controls and versus a high-fiber diet for 8-10 weeks to test the effects of these interventions on vascular function and explore potential mechanisms. Of the various differences in the gut microbiomes of old mice, lower SCFA-producing capacity (taxonomic abundance and functional pathways) stood out as a key feature related to worse arterial function after adjusting for age. Acetate supplementation and a high-fiber diet reversed ~30% of the age-related increase in aortic pulse wave velocity (stiffness) and fully restored carotid artery endothelium-dependent dilation (endothelial function) to young levels. Acetate and a high-fiber diet reduced age-related increases in systemic inflammation. We also found that improvements in endothelial function were likely mediated by suppressed early growth response-1 signaling using innovative siRNA-based knockdown in isolated arteries. There were no effects of the interventions in young mice. Acetate supplementation was comparably effective for ameliorating arterial dysfunction with aging as a high-fiber diet and thus shows promise for reducing CVD risk in older adults., Competing Interests: Disclosures Rob Knight, a scientific advisory board member and consultant for BiomeSense, Inc., has equity and receives income. He is a scientific advisory board member and has equity in GenCirq. He is a consultant and scientific advisory board member for DayTwo and receives income. He has equity in and acts as a consultant for Cybele. He is a cofounder of Biota, Inc., and has equity. He is a cofounder of Micronoma, has equity, and is a scientific advisory board member. The terms of these arrangements have been reviewed and approved by the University of California, San Diego, in accordance with its conflict of interest policies.

Background: Here, we assessed the role of cellular senescence and the senescence associated secretory phenotype (SASP) in age-related aortic stiffening and endothelial dysfunction., Methods: We studied young (6-8 mo) and old (27-29 mo) p16-3MR mice, which allows for genetic-based clearance of senescent cells with ganciclovir (GCV). We also treated old C57BL/6N mice with the senolytic ABT-263., Results: In old mice, GCV reduced aortic stiffness assessed by aortic pulse wave velocity (PWV; 477±10 vs. 382±7 cm/s, P <0.05) to young levels (old-GCV vs. young-vehicle, P =0.35); ABT-263 also reduced aortic PWV in old mice (446±9 to 356±11 cm/s, P <0.05). Aortic adventitial collagen was reduced by GCV ( P <0.05) and ABT-263 ( P =0.12) in old mice. To show an effect of the circulating SASP, we demonstrated that plasma exposure from Old-vehicle p16-3MR mice, but not from Old-GCV mice, induced aortic stiffening assessed ex vivo (elastic modulus; P <0.05). Plasma proteomics implicated glycolysis in circulating SASP-mediated aortic stiffening. In old p16-3MR mice, GCV increased endothelial function assessed via peak carotid artery endothelium-dependent dilation (EDD; Old-GCV, 94±1% vs. Old-vehicle, 84±2%, P <0.05) to young levels (Old-GCV vs. young-vehicle, P =0.98), and EDD was higher in old C57BL/6N mice treated with ABT-263 vs. vehicle (96±1% vs. 82±3%, P <0.05). Improvements in endothelial function were mediated by increased nitric oxide (NO) bioavailability ( P <0.05) and reduced oxidative stress ( P <0.05). Circulating SASP factors related to NO signaling were associated with greater NO-mediated EDD following senescent cell clearance., Conclusions: Cellular senescence and the SASP contribute to vascular aging and senolytics hold promise for improving age-related vascular function., Competing Interests: Disclosures None.

The aorta stiffens with aging in both men and women, which predicts cardiovascular mortality. Aortic wall structural and extracellular matrix (ECM) remodeling, induced in part by chronic low-grade inflammation, contribute to aortic stiffening. Male mice are an established model of aortic aging. However, there is little information regarding whether female mice are an appropriate model of aortic aging in women, which we aimed to elucidate in the present study. We assessed two strains of mice and found that in C57BL/6N mice, in vivo aortic stiffness (pulse wave velocity, PWV) was higher with aging in both sexes, whereas in B6D2F1 mice, PWV was higher in old versus young male mice, but not in old versus young female mice. Because the age-related stiffening that occurs in men and women was reflected in male and female C57BL/6N mice, we examined the mechanisms of stiffening in this strain. In both sexes, aortic modulus of elasticity (pin myography) was lower in old mice, occurred in conjunction with and was related to higher plasma levels of the elastin-degrading enzyme matrix metalloproteinase-9 (MMP-9), and was accompanied by higher numbers of aortic elastin breaks and higher abundance of adventitial collagen-1. Plasma levels of the inflammatory cytokines interferon-γ, interleukin 6, and monocyte chemoattractant protein-1 were higher in both sexes of old mice. In conclusion, female C57BL/6N mice exhibit aortic stiffening, reduced modulus of elasticity and structural/ECM remodeling, and associated increases in MMP-9 and systemic inflammation with aging, and thus are an appropriate model of aortic aging in women. NEW & NOTEWORTHY Our study demonstrates that with aging, female C57BL/6N mice exhibit higher in vivo aortic stiffness, reduced modulus of elasticity, aortic wall structural and extracellular matrix remodeling, and elevations in systemic inflammation. These changes are largely reflective of those that occur with aging in women. Thus, female C57BL/6N mice are a viable model of human aortic aging and the utility of these animals should be considered in future biomedical investigations.