Yu and Richardson et al. find that restriction of dietary isoleucine or valine promotes metabolic health in mice and that restriction of dietary isoleucine is required for the metabolic benefits of a low-protein diet. Furthermore, higher dietary isoleucine levels are associated with increased BMI in humans.

Protein restricted (PR) diets promote health and longevity in many species. While the precise components of a PR diet that mediate the beneficial effects to longevity have not been defined, we recently showed that many metabolic effects of PR can be attributed to reduced dietary levels of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine. Here, we demonstrate that restricting dietary BCAAs increases the survival of two different progeroid mouse models, delays frailty and promotes the metabolic health of wild-type C57BL/6J mice when started in midlife, and leads to a 30% increase in lifespan and a reduction in frailty in male, but not female, wild-type mice when fed lifelong. Our results demonstrate that restricting dietary BCAAs can increase healthspan and longevity in mice, and suggest that reducing dietary BCAAs may hold potential as a translatable intervention to promote healthy aging.

Calorie restriction (CR) promotes healthy aging in diverse species. Recently, it has been shown that fasting for a portion of each day has metabolic benefits and promotes lifespan. These findings complicate the interpretation of rodent CR studies, in which animals typically eat only once per day and rapidly consume their food, which collaterally imposes fasting. Here, we show that a prolonged fast is necessary for key metabolic, molecular and geroprotective effects of a CR diet. Using a series of feeding regimens, we dissect the effects of calories and fasting, and proceed to demonstrate that fasting alone recapitulates many of the physiological and molecular effects of CR. Our results shed new light on how both when and how much we eat regulate metabolic health and longevity, and demonstrate that daily prolonged fasting, and not solely reduced calorie intake, is likely responsible for the metabolic and geroprotective benefits of a CR diet.

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The extracellular matrix (ECM) of the brain comprises unique glycan "sulfation codes" that influence neurological function. Perineuronal nets (PNNs) are chondroitin sulfate-glycosaminoglycan (CS-GAG) containing matrices that enmesh neural networks involved in memory and cognition, and loss of PNN matrices is reported in patients with neurocognitive and neuropsychiatric disorders including Alzheimer's disease (AD). Using liquid chromatography tandem mass spectrometry (LC-MS/MS), we show that patients with a clinical diagnosis of AD-related dementia undergo a recoding of their PNN-associated CS-GAGs that correlates to Braak stage progression, hyperphosphorylated tau (p-tau) accumulation, and cognitive impairment. As these CS-GAG sulfation changes are detectable prior to the regional onset of classical AD pathology, they may contribute to the initiation and/or progression of the underlying degenerative processes and implicate the brain matrix sulfation code as a key player in the development of AD clinicopathology.

Around the globe, human life expectancy increased by almost 20 years between 1950 (Collaborators, 2018. Despite the effect of the global COVID-19 pandemic, which has caused life expectancy in the United States to slightly decline (Arias et al., 2021), advances in medicine have shifted population demographics, and humans older than 65 now represent the fastest growing age group worldwide (United Nations, 2019). As a result, the portion of deaths attributed to noncommunicable diseases, such as age-related diseases, has risen and will continue to rise (Foreman et al., 2018).Though human life expectancy has largely increased, the prevalence of obesity and related disorders has grown rapidly, threatening the quality and duration of healthy years for an ever-expanding aged population. Obesity is more than tripled in men and doubled in women from 1975 to 2014, and 43% of American adults aged 40-59 are now obese (Collaboration, 2016). Obesity is increasingly impacting younger individuals, with about 40% of children now overweight

Several distinct strategies produce and conserve heat to maintain the body temperature of mammals, each associated with unique physiologies, with consequences for wellness and disease susceptibility r Highly regulated properties of skin offset the total requirement for heat production r We hypothesize that the adipose component of skin is primarily responsible for modulating heat flux; here we evaluate the relative regulation of adipose depots in mouse and human, to test their recruitment to heat production and conservation r We found that insulating mouse dermal white adipose tissue accumulates in response to environmentally and genetically induced cool stress; this layer is one of two adipose depots closely apposed to mouse skin, where the subcutaneous mammary gland fat pads are actively recruited to heat production r In contrast, the body-wide adipose depot associated with human skin produces heat directly, potentially creating an alternative to the centrally regulated brown adipose tissue Ildiko Kasza, PhD, studied biology at the Semmelweis Medical University, Budapest, Hungary, and prepared her PhD thesis on the role of the cellular cholesterol exporter, ABCA1, in cholesterol homeostasis in humans. She started her postdoctoral career with Dr CM Alexander at the University of Wisconsin, where she focused on the mechanisms underlying the profound tumour resistance of mice with a syndecan-1 mutation. She discovered a novel link between the cancer resistance phenotype and the depletion of a specific fat depot under the skin, the so-called dermal white adipose tissue, leading to systemic cold stress. More specifically, she is interested in mammalian skin as a key metabolic regulator, as well as its influence on human disease susceptibility.This article was first published as a preprint.