Protein restriction and branched‐chain amino acid restriction promote geroprotective shifts in metabolism

Abstract

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

Resistance exercise protects mice from protein-induced fat accretion

“…In model organisms and humans, dietary protein is a critical regulator of a wide variety of biological processes that determine metabolic health and lifespan (Trautman et al, 2022). Low protein diets promote healthspan and lifespan in flies and rodents (Fontana et al, 2016; Hill et al, 2022a; Solon-Biet et al, 2014), and emerging data suggests the same may be true for humans (Ferraz-Bannitz et al, 2022; Fontana et al, 2016; Laeger et al, 2014; Levine et al, 2014; Mair et al, 2005; Yu et al, 2020).…”

SLC3A2 N-glycosylation and alternate evolutionary trajectories for amino acid metabolism

“…Indeed, SLC3A2 function connects these two recognized features of metabolism associated with longevity: - regulation of BCAA levels - thereby mTOR activity, and cysteine flux to GSH synthesis. C4 to C6 acyl-CoA biproducts of Leu, Ile, Val, Phe, and Tyr catabolism can compete for carnitine and interfere with fatty acid metabolism (50,90,91), which is critical for both fat stores and fueling muscle in prolonged flight. Indeed, reducing dietary BCAA in mice increases fatty acid catabolism, reduces triglyceride stores, and improves insulin sensitivity (92).…”

Dietary change without caloric restriction maintains a youthful profile in ageing yeast

“…We doubt that any epigenetic mark at the rDNA or elsewhere would be sufficiently stable or asymmetrically segregated to maintain this trajectory. Loss of vacuolar acidity has been proposed to drive ageing in yeast and could force cells permanently into the pathological trajectory, as the vacuole regulates iron availability and a lack of iron causes numerous cellular defects (Chen et al, 2020;Hughes and Gottschling, 2012;Ramos-Alonso et al, 2020;Veatch et al, 2009). Iron availability is low in the short-lived trajectory, iron importer subunits are upregulated both in single cell RNA-seq of slow dividing ageing cells and in our RNA-seq analysis of low WGA cells, and we observe that over-expression of the iron-dependent Hap4 transcription factor cannot maintain expression of target genes in cells on the pathological ageing trajectory Zhang et al, 2020).…”

“…Dietary restriction can improve ageing health in eukaryotes ranging from budding yeast to primates and even humans, but remains an unrealistic approach for improving ageing health in human populations as this sacrifice requires substantial commitment (Didier et al, 2016;Fontana and Klein, 2007;Fontana et al, 2010;Green et al, 2022;Hofer et al, 2022). However, the beneficial effects of dietary restriction are not simply due to a reduction in calories as equivalent effects can be achieved through limiting or even tailoring amino acid intake, indicating that improved ageing health results from altered metabolic state rather than minimal energy intake (Jiang et al, 2000;Mair et al, 2005;Trautman et al, 2022). Improved ageing health may therefore be achievable in humans through optimising diet, but this will require a much better understanding of the interplay between diet and the biological mechanisms leading to ageing pathology (Lee et al, 2021).…”

“…Mother cells maintain a rapid and uniform cell cycle for most of their replicative lifespan but the cell cycle slows dramatically in the last few divisions (Egilmez and Jazwinski, 1989;Fehrmann et al, 2013;Mortimer and Johnston, 1959), a point designated the Senescence Entry Point (SEP) that is coincident with the appearance of apparently pathological markers including mitochondrial protein foci formation and nucleolar expansion (Fehrmann et al, 2013;Morlot et al, 2019). Many other changes occur during replicative ageing, including cell growth (Mortimer and Johnston, 1959;Neurohr et al, 2019), loss of mitochondrial membrane potential (Veatch et al, 2009), mitochondrial fragmentation (Lam et al, 2011), loss of vacuolar acidity (Hughes and Gottschling, 2012), nuclear pore disruption (Meinema et al, 2022), and protein oxidation and aggregation (Aguilaniu et al, 2003;Erjavec et al, 2008), each of which likely contributes to the eventual loss of replicative potential, but how these relate to each other or to the extension of cell cycle timing at the SEP remains largely unknown.…”