Reduced growth hormone signaling and methionine restriction: interventions that improve metabolic health and extend life span

Abstract

Interventions that improve health are often associated with longevity. Reduced growth hormone signaling has been shown to increase life span in mice by over 50%. Similarly, reductions in dietary intake of methionine, in rats and mice, result in life-span extension. Many factors affect metabolic health, mitochondrial function, and resistance to stressors, each of which influence aging and life span. This paper presents a comparison of these two interventions, as well as the results of a study combining these interventions, to understand potential mechanisms underlying their effectiveness in enhancing healthy aging.

Metabolic adaptation of short‐living growth hormone transgenic mice to methionine restriction and supplementation

“…In the absence of GH signaling, GSH is elevated and contributes to enhanced stress resistance likely via NRF2 activation . MET restriction in normal mice does not alter cellular stress resistance suggesting that GH may be the key factor in managing resistance . Related GSH metabolites within the γ‐glutamyl cycle (glutamate and glutamine) support this evidence and indicate that restricting MET increases metabolite levels in the presence of GH whereas in its absence, the system does not detect dietary AA differences.…”

“…Many but not all of the health benefits of MET restriction and GH deficiency are shared and include improvements to insulin sensitivity, reduced tumor incidence, and delays in aging of the immune system . To better understand the metabolic responses imposed by different levels of dietary MET in the context of accelerated aging and age‐related disease, we conducted studies feeding GH Tg and WT animals different levels of MET for 8 weeks.…”

Age Drives Distortion of Brain Metabolic, Vascular and Cognitive Functions, and the Gut Microbiome

“…Excessive methionine has been considered to be accountable for increased mitochondrial ROS production, which in turn enhances oxidative stress and inflammation (Jaeschke, 2011 ; Schweinberger and Wyse, 2016 ; Palermo et al, 2017 ). Interestingly, previous studies have shown that methionine restriction can lead to increased longevity by decreasing mitochondrial complex IV activity and accumulation of ROS (Kozieł et al, 2014 ; Brown-Borg, 2016 ).…”

Cutting back on the essentials: Can manipulating intake of specific amino acids modulate health and lifespan?

“…Downstream effectors of mTOR, TORC1 and TORC2 coordinate anabolic and catabolic processes in response to energy status, nutrients and growth (Laplante and Sabatini, 2012). In contrast to other longevity mutants however, phosphorylated mTOR and AMPK (energy status sensor) are similar between methionine restriction and mice fed methionine-replete diets (Sun et al, 2009; Brown-Borg, 2015; Dominick et al, 2015; Gesing et al, 2011; Sharp and Bartke, 2005; Wang and Miller, 2012; Kim and Guan, 2011). The lack of a difference in AMPK may explain the decrease in fatty acid oxidation described in these animals as opposed to the upregulation found in long living dwarf mice (Perrone et al, 2012; Stauber et al, 2005; Bartke and Westbrook, 2012).…”

“…Increased thermogenesis rather than ATP formation may be causally linked to the observed decline in oxidative damage in methionine-restricted rats (Maddineni et al, 2013; Sanchez-Roman et al, 2012). Redox signaling through ubiquinone 9 and NRF2-dependent phase II antioxidants, including NAD(P)H dehydrogenase quinone 1 (NQO1), glutathione-S-transferase (GST), and heme oxygenase 1 (HO1) is also upregulated in methionine-restricted mice, traits shared with other long-lived vertebrates (Lewis et al, 2010; Jove et al, 2013; Mitchell et al, 2007; Brown-Borg et al, 2015). …”