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Senescent cells accumulate with age in vertebrates and promote aging largely through their senescence‐associated secretory phenotype (SASP). Many types of stress induce senescence, including genotoxic stress. ERCC1‐XPF is a DNA repair endonuclease required for multiple DNA repair mechanisms that protect the nuclear genome. Humans or mice with reduced expression of this enzyme age rapidly due to increased levels of spontaneous, genotoxic stress. Here, we asked whether this corresponds to an increased level of senescent cells. p16Ink4a and p21Cip1 mRNA were increased ~15‐fold in peripheral lymphocytes from 4‐ to 5‐month‐old Ercc1−/∆ and 2.5‐year‐old wild‐type (WT) mice, suggesting that these animals exhibit a similar biological age. p16Ink4a and p21Cip1 mRNA were elevated in 10 of 13 tissues analyzed from 4‐ to 5‐month‐old Ercc1−/∆ mice, indicating where endogenous DNA damage drives senescence in vivo. Aged WT mice had similar increases of p16Ink4a and p21Cip1 mRNA in the same 10 tissues as the mutant mice. Senescence‐associated β–galactosidase activity and p21Cip1 protein also were increased in tissues of the progeroid and aged mice, while Lamin B1 mRNA and protein levels were diminished. In Ercc1−/Δ mice with a p16Ink4a luciferase reporter, bioluminescence rose steadily with age, particularly in lung, thymus, and pancreas. These data illustrate where senescence occurs with natural and accelerated aging in mice and the relative extent of senescence among tissues. Interestingly, senescence was greater in male mice until the end of life. The similarities between Ercc1−/∆ and aged WT mice support the conclusion that the DNA repair‐deficient mice accurately model the age‐related accumulation of senescent cells, albeit six‐times faster. Senescent cells contribute to aging and its associated morbidities. Senescent cells accumulate in vertebrates with aging. Here, we survey where (in what tissues) senescence occurs with aging in mice, by measuring p16Ink4a and p21Cip1 mRNA. A similar survey in Ercc1−/Δ mice illustrates where (in what tissues) senescence occurs in vivo as a consequence of endogenous DNA damage.

Caloric restriction slows or prevents Alzheimer’s disease in animal models. Calorie restriction is typically implemented in rodents through feeding once per day; as the animals quickly consume their food, they are subject to a prolonged self-imposed fasting period between meals. Here, we examine the distinct contributions of fasting and reduced calories to the beneficial effects of calorie restriction on Alzheimer’s disease by placing male and female 3xTg and non-transgenic control mice on a series of diet regimens enabling us to dissect the effects of calories and fasting. We find that reducing calories alone improves body weight and glucose tolerance. However, a prolonged fast between meals is necessary for many of the benefits of calorie restriction, including improved insulin sensitivity, reduced Alzheimer’s pathology, improved neuroprotective signaling, and improved cognition. Overall, our results suggest that both when and how much we eat may influence the development and progression of Alzheimer’s disease. Caloric restriction improves Alzheimer’s Disease outcomes in mice, but this diet not only reduces calories, but imposes a prolonged fast between meals. Here, the authors show this fast is essential to improve Alzheimer’s pathology and cognition.

Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and dietary protein restriction extends the lifespan and healthspan of mice. In this study, we examined the effect of protein restriction (PR) on metabolic health and the development and progression of Alzheimer’s disease (AD) in the 3xTg mouse model of AD. Here, we show that PR promotes leanness and glycemic control in 3xTg mice, specifically rescuing the glucose intolerance of 3xTg females. PR induces sex-specific alterations in circulating and brain metabolites, downregulating sphingolipid subclasses in 3xTg females. PR also reduces AD pathology and mTORC1 activity, increases autophagy, and improves the cognition of 3xTg mice. Finally, PR improves the survival of 3xTg mice. Our results suggest that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD. There is growing need for ways to slow or prevent Alzheimer’s disease (AD). Here, the authors demonstrate that a low protein diet can protect against metabolic dysfunction, slow AD progression, and preserve cognitive function in a mouse model of AD.

Dietary protein regulates metabolic health and aging, with many benefits of a low protein diet resulting from reduced consumption of the three branched‐chain amino acids (BCAAs), leucine, isoleucine, and valine. Each BCAA has distinct physiological and molecular effects, and while restriction of protein or all three BCAAs improves cognition in mouse models of Alzheimer's disease (AD), the role of each individual BCAA on AD is unknown. Here, we investigate the impact of restricting leucine, isoleucine, or valine on metabolism, AD pathology, molecular signaling, and cognition in male and female 3xTg AD mice. Mice were fed BCAA‐restricted diets for nine months starting at six months of age. Restriction of either isoleucine or valine, but not leucine, improved metabolic health. We observed distinct, BCAA‐specific effects on AD pathology, molecular signaling, and gene expression in both sexes as well as shared molecular responses in males. Restricting any BCAA improved short‐term memory in males, with isoleucine having the strongest effect, while valine restriction led to the greatest cognitive benefits for females. These findings suggest that targeted BCAA restriction, particularly of isoleucine or valine, may form the basis of a novel sex‐specific approach to prevent or delay AD. Protein restriction (PR) slows Alzheimer's disease (AD) in mice, and other benefits of PR are due to decreased branched‐chain amino acids (BCAAs). We show that restricting any BCAA has benefits, with sex‐ and BCAA‐specific impacts on pathology, molecular signaling, and cognition. These findings highlight dietary composition as critical in the development and progression of AD, and could guide future therapies.

Dietary protein is a key regulator of healthy aging in both mice and humans. In mice, reducing dietary levels of the branched‐chain amino acids (BCAAs) recapitulates many of the benefits of a low protein diet; BCAA‐restricted diets extend lifespan, reduce frailty, and improve metabolic health, while BCAA supplementation shortens lifespan, promotes obesity, and impairs glycemic control. Recently, high protein diets have been shown to promote cellular senescence, a hallmark of aging implicated in many age‐related diseases, in the liver of mice. Here, we test the hypothesis that the effects of high protein diets on metabolic health and on cellular senescence are mediated by BCAAs. We find that reducing dietary levels of BCAAs protects male mice from the negative metabolic consequences of both normal and high protein diets. Further, we identify tissue‐specific effects of BCAAs on cellular senescence, with restriction of all three BCAAs—but not individual BCAAs—protecting from hepatic cellular senescence while potentiating cellular senescence in white adipose tissue. We also find that these effects are sex‐specific. We find that the effects of BCAAs on hepatic cellular senescence are cell‐autonomous, with lower levels of BCAAs protecting cultured cells from antimycin‐A induced senescence. Our results demonstrate a direct effect of a specific dietary component on a hallmark of aging and suggest that cellular senescence may be highly susceptible to dietary interventions. Restriction of dietary BCAAs protects male mice from the metabolic consequences of both normal‐ and high‐protein diets. BCAA restriction also protects from hepatic cellular senescence in vivo and in vitro, especially in the context of mitochondrial stress.

Caloric restriction (CR) extends the health and lifespan of diverse species. When fed once daily, CR‐treated mice rapidly consume their food and endure a prolonged fast between meals. As fasting is associated with a rise in circulating ketone bodies, we investigated the role of ketogenesis in CR using mice with whole‐body ablation of Hmgcs2, the rate‐limiting enzyme producing the main ketone body β‐hydroxybutyrate (βHB). Here, we report that Hmgcs2 is largely dispensable for many metabolic benefits of CR, including CR‐driven changes in adiposity, glycemic control, liver autophagy, and energy balance. Although we observed sex‐specific effects of Hmgcs2 on insulin sensitivity, fuel selection, and adipocyte gene expression, the overall physiological response to CR remained robust in mice lacking Hmgcs2. To gain insight into why the deletion of Hmgcs2 does not disrupt CR, we measured fasting βHB levels as mice initiated a CR diet. Surprisingly, as mice adapt to CR, they no longer engage in high levels of ketogenesis during the daily fast. Our work suggests that the metabolic benefits of long‐term CR are not mediated by ketogenesis. In this study, we demonstrated that metabolic responses to a daily‐fed caloric restriction (CR) protocol remain robust in mice that cannot engage in canonical ketogenesis. This surprising finding is due to mice physiologically adapting to the daily bouts of fasting during CR by downregulating ketone production.

Restricting the intake of protein or the branched-chain amino acid isoleucine promotes healthspan and extends lifespan in young or adult mice. However, their effects when initiated in aged animals are unknown. Here we investigate the consequences of consuming a diet with 67% reduction of all amino acids (low AA) or of isoleucine alone (low Ile), in male and female C57BL/6J.Nia mice starting at 20 months of age. Both dietary regimens effectively promote overall metabolic health without reducing calorie intake. Both low AA and low Ile diets improve aspects of frailty and slow multiple molecular indicators of aging rate; however, the low Ile diet reduces grip strength in both sexes and has mixed, sexually dimorphic effects on the heart. These results demonstrate that low AA and low Ile diets can promote aspects of healthy aging in aged mice and suggest that similar interventions might promote healthy aging in older adults. Yeh et al. explore the effects of restricting dietary protein, or isoleucine specifically, in aged mice. They uncover benefits to metabolic health and certain indicators of aging and a sexually dimorphic effect on the heart.

Age is the greatest risk factor for Alzheimer’s disease (AD) as well as for other disorders that increase the risk of AD such as diabetes and obesity. There is growing interest in determining if interventions that promote metabolic health can prevent or delay AD. Acarbose is an anti-diabetic drug that not only improves glucose homeostasis, but also extends the lifespan of wild-type mice. Here, we test the hypothesis that acarbose will not only preserve metabolic health, but also slow or prevent AD pathology and cognitive deficits in 3xTg mice, a model of AD, fed either a Control diet or a high-fat, high-sucrose Western diet (WD). We find that acarbose decreases the body weight and adiposity of WD-fed 3xTg mice, increasing energy expenditure while also stimulating food consumption, and improves glycemic control. Both male and female WD-fed 3xTg mice have worsened cognitive deficits than Control-fed mice, and these deficits are ameliorated by acarbose treatment. Molecular and histological analysis of tau and amyloid pathology identified sex-specific effects of acarbose which are uncoupled from the dramatic improvements in cognition in females, suggesting that the benefits of acarbose on AD may be largely driven by improved metabolic health. In conclusion, our results suggest that acarbose may be a promising intervention to prevent, delay, or even treat AD, especially in individuals consuming a WD.

The proportion of individuals age 65 and older as well as the proportion of individuals considered obese is rapidly increasing worldwide. These individuals are more susceptible to developing age-related morbidities, which can put a strain on our healthcare system. In the US alone, obesity-related direct medical costs reached over $385 billion dollars in 2024 while ninety percent of the nation's annual health care expenditures are for people with chronic and mental health conditions. Thus, creative solutions to promote healthy aging and longevity are greatly needed. Dietary interventions are potent interventions to promote healthy aging. The gold standard dietary intervention, calorie restriction (CR), has been shown to rapidly improve metabolic health and extend lifespan in multiple species. While CR has been studied for over 100 years, the mechanisms by which it improves metabolic health and longevity are still not fully known. Therefore, I decided to test whether fibroblast growth factor 21 (FGF21), an energy balance hormone that is induced by CR in a sex-specific manner, is necessary for the metabolic health benefits of CR. I hypothesized that loss of Fgf21 will have sex-dependent impacts on the response to CR, particularly with respect to metabolic health improvements. Utilizing Fgf21-/- mice, I found that FGF21 is largely dispensable for the metabolic health benefits of CR in both sexes. Interestingly, while CR does not induce FGF21 in males, loss of Fgf21 blunts the beiging of inguinal white adipose tissue (iWAT) in response to CR. This study demonstrated that the metabolic benefits of CR is not due to FGF21, despite its role on iWAT beiging. While FGF21 is not necessary for CR-related health improvements, an alternative dietary intervention, called protein restriction (PR), requires FGF21 and has been shown to have similar effects on extending health and longevity. The Lamming lab has previously shown that the benefits of PR on healthspan and lifespan can be replicated through the restriction of the branched-chain amino acids (i.e. leucine, isoleucine and valine). Further, BCAA restriction has been shown to rapidly reduce adiposity and improve glycemic control in diet-induce obese (DIO) mice, providing a potential translatable intervention to combat obesity. However, adherence to a long-term intervention is difficult, and in humans, cycling between diets with weight gain and weight loss periods, or “yo-yo dieting,” has become a common trend. Therefore, I wanted to test how yo-yo dieting using short-term BCAA restriction in DIO mice affects long-term health. I found that acute BCAA restriction (3 weeks) rapidly improves metabolic health. Further, after being placed back onto the western diet with full BCAAs, termed “BCAA repletion,” I found that previously-BCAA-restricted animals still had better glucose tolerance and increased energy expenditure as well as smaller fat mass and hepatic lipid droplet size. These physiological changes were also accompanied by a metabolic reprogramming of the liver; my joint pathway analysis on persistently downregulated genes and metabolites displayed protection from metabolic dysfunction-related pathways, such as obesity, type 2 diabetes and fatty liver disease. This study demonstrates that short-term BCAA restriction has long-term benefits on metabolic health. The joint pathway analysis also displayed protection from cellular senescence, one of the hallmarks of aging. Cellular senescence is a cell-cycle-arrested state that produced a senescence-associated secretory phenotype (SASP), thought to play a role in chronic inflammation seen with age and is also implicated in multiple age-related diseases. Dietary protein consumption is associated with increased senescence accumulation in the liver. Because I found that acute BCAA restriction leads to protection from the cellular senescence pathway, I hypothesized that the increased hepatic senescence caused by higher protein consumption is mediated by increased BCAAs. Indeed, I found that BCAAs rather than protein promotes hepatic senescence in part by increasing mitochondrial dysfunction in the hepatocytes of the liver. Interestingly, I also found that BCAA restriction promotes iWAT senescence, despite an overall improvement in metabolic health in these same animals. This study demonstrates the importance of assessing multiple tissues in response to an intervention. Lastly, each of the individual BCAAs has unique responses on metabolic health. Restriction of isoleucine (Ile-R) and valine (Val-R) have both been shown to replicate the benefits of BCAA restriction on metabolic health, with Ile-R alone capable of extending healthspan and lifespan in mice. In humans, intake of isoleucine and valine is associated with body mass index. However, despite its known role on insulin resistance and fatty liver disease, valine is understudied and its impact on healthspan and lifespan is unknown. Therefore, I hypothesized that Val-R extends healthspan and lifespan in mice similarly to BCAA restriction and Ile-R. I found that Val-R prevents body weight and fat mass accretion as well as improves overall metabolic health. Val-R reduces frailty, cancer incidence, senescence and neuroinflammation. Interestingly, I found a male-specific lifespan extension in response to Val-R, replicating the lifespan-related effects of PR and BCAA restriction. Because it is important to test how an intervention affects multiple tissues, we assessed Val-R at the transcriptional level in the liver, brown adipose tissue and muscle. Using an inter-tissue network analysis, we found a liver-specific cluster of mitochondrial metabolism-related genes to be a central node. In isolated liver mitochondria, we found a male-specific increase in mitochondrial respiration, suggesting that the male-specific lifespan extension by Val-R may be mediated in part by an upregulation of hepatic mitochondrial respiration. This dissertation demonstrates the influence of diet on metabolic health and longevity. Whether the diet is short-term or long-term, I also found sex- and tissue-specific changes. While CR induces molecular and morphological effects on the iWAT in males, acute BCAA restriction in DIO mice. While acute BCAA restriction only persistently alters BAT thermogenesis after BCAA repletion in males, long-term Val-R demonstrates multi-tissue effects on thermogenesis, with an activation of BAT in both sexes, a partial engagement of UCP1 in iWAT and a male-specific increase in SERCA2-mediated thermogenesis in muscle. Further, both BCAA restriction and Val-R cause hepatic reprogramming, leading to the downregulation of pathways related to metabolic dysfunction and cellular senescence, potentially mediated by altered mitochondrial metabolism. Sex- and tissue-specific alterations will likely continue to be discovered across interventions. This study highlights the importance of an individualized medicine approach to designing dietary strategies to combat aging and obesity in humans.

Dietary protein intake mediates healthy aging in diverse species, with consumption of a low protein (LP) diet improving metabolic health in both humans and mice. In mice, the benefits of LP diets are sex-specific, with males exhibiting a stronger response to a LP diet than females. The reason for this sexually dimorphic response is unknown, but we hypothesized that sex hormones might be responsible for this difference. Here, we tested the role of sex hormones in the response to a LP diet by feeding intact and gonadectomized mice of both sexes either a Control (21% of calorie from protein) or LP (7% of calories from protein) diet, and assessing the effects on weight, body composition, glycemic control, and energy balance over the course of three months, followed by molecular and histological analysis of tissues from each group. We confirm that males show a stronger metabolic response to an LP diet than females, but that ovariectomy sensitizes female mice to the metabolic effects of an LP diet, making them respond more similarly to males; conversely, castration does not substantially impact the response of males to an LP diet. Molecularly, we find that gonadectomy and sex are important interactors that mediate the response of mechanistic target of rapamycin (mTOR) signaling, lipid homeostasis, and thermogenesis to an LP diet. Together, this data shows that the resistance of female mice to an LP diet is mediated by ovarian hormones and suggests the possibility that older female humans might receive enhanced benefits from LP diet feeding.