Branched-chain amino acid catabolism is a conserved regulator of physiological ageing

Abstract

Ageing has been defined as a global decline in physiological function depending on both environmental and genetic factors. Here we identify gene transcripts that are similarly regulated during physiological ageing in nematodes, zebrafish and mice. We observe the strongest extension of lifespan when impairing expression of the branched-chain amino acid transferase-1 (bcat-1) gene in C. elegans, which leads to excessive levels of branched-chain amino acids (BCAAs). We further show that BCAAs reduce a LET-363/mTOR-dependent neuro-endocrine signal, which we identify as DAF-7/TGFβ, and that impacts lifespan depending on its related receptors, DAF-1 and DAF-4, as well as ultimately on DAF-16/FoxO and HSF-1 in a cell-non-autonomous manner. The transcription factor HLH-15 controls and epistatically synergizes with BCAT-1 to modulate physiological ageing. Lastly and consistent with previous findings in rodents, nutritional supplementation of BCAAs extends nematodal lifespan. Taken together, BCAAs act as periphery-derived metabokines that induce a central neuro-endocrine response, culminating in extended healthspan.

SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion

“…Further, proper control of leucine catabolism is important for overall healthy aging (Mansfeld et al, 2015). Thus, we set out to identify physiological consequences of dysregulated leucine catabolism in SIRT4KO mice.…”

Resilience to aging in the regeneration‐capable flatworm Macrostomum lignano

“…ns, not significant.aThis study.bRangaraju et al., 2015.cNalapareddy et al., 2017.dBochkis et al., 2014.eMansfeld et al., 2015.…”

“…To evaluate whether the observed enrichments for GenAge and genome maintenance genes among genes differentially expressed with age in M. lignano are also typical for conventional model organisms, we re‐analyzed several publicly available aging RNA‐seq datasets, including C. elegans (Rangaraju et al., 2015) , mouse intestinal stem cells (Nalapareddy et al., 2017) and liver (Bochkis, Przybylski, Chen & Regev, 2014), and mouse and zebrafish skin (Mansfeld et al., 2015). In contrast to M. lignano , none of these datasets show enrichment for GenAge genes among genes upregulated with age, and in C. elegans and zebrafish skin, this category is even significantly underrepresented (Table 1).…”

“…For the analysis of gene set enrichment in conventional model organisms during aging, we retrieved from NCBI Short Read archive RNA‐seq for C. elegans (Rangaraju et al., 2015), mouse intestinal stem cells (Nalapareddy et al., 2017), mouse liver (Bochkis et al., 2014), and mouse and zebrafish skin (Mansfeld et al., 2015). Annotated genomes were retrieved from Ensembl, and RNA‐seq data were mapped and quantified using star v.2.5.2b (Dobin et al., 2013).…”

Improving Longevity with Metadichol® by Inhibiting the BCAT1 Gene

“…BCAA catabolism and specifically increased activity of the corresponding enzyme, BCAT1 has been linked to various diseases (Table 1) in aging [2,3] and pathological states [4], including accelerated growth of malignant gliomas [5], decreased sepsis survival [6] and increased accumulation of liver fat [7], the latter being linked to a number of metabolic diseases [8,9]. Consistently, systemic disruption of one BCAT iso-form [10], namely BCATm, in mice increases energy expenditure and reduces body weight [11] and cancer [12,13].…”