Amino Acid Availability Is Not Essential for Life-Span Extension by Dietary Restriction in the Fly

Abstract

Dietary restriction (DR) is one of the most potent ways to extend health- and lifespan. Key progress in understanding the mechanisms of DR, and ageing more generally, was made when dietary protein, and more specifically essential amino acids (EAA), were identified as the dietary component to restrict to obtain DR’s health and lifespan benefits. This role of dietary amino acids has influenced work on ageing mechanisms, especially in nutrient sensing, e.g. Tor and insulin(-like) signalling networks. Experimental biology in Drosophila melanogaster has been instrumental in generating and confirming the hypothesis that EAA availability is important in ageing. Here, we expand on previous work testing the involvement of EAA in DR through large scale (N=6,238) supplementation experiments across four diets and two genotypes in female flies. Surprisingly, we find that EAA are not essential to DR’s lifespan benefits. Importantly, we do identify the fecundity benefits of EAA supplementation suggesting the supplemented EAA were bioavailable. Furthermore, we find that the effects of amino acids on lifespan vary by diet and genetic line studied and that at our most restricted diet fecundity is constrained by other nutrients than EAA. We suggest that DR for optimal health is a concert of nutritional effects, orchestrated by genetic, dietary and other environmental interactions. Our results question the universal importance of amino acid availability in the biology of ageing and DR.

Dietary restriction extends lifespan across different temperatures in the fly

“…First we wanted to confirm that we used a strain responsive to DR at the lab standard 25°C. In a strain (ywR) we have used extensively before (Drake & Simons, 2023; Gautrey & Simons, 2022) we found a significant DR longevity response in three other separate (before unpublished) experiments we previously conducted (P < 0.0001; Table 1). These experiments compared 2% yeast (our standard DR diet) to 8% yeast (the standard ad libitum diet used by our lab) (McCracken, Buckle, et al, 2020) (Figure 1).…”

Dietary restriction extends lifespan across different temperatures in the fly

“…First we wanted to confirm that we used a strain responsive to DR at the lab standard 25°C. In a strain (ywR), we have used extensively before (Drake & Simons, 2023;Gautrey & Simons, 2022) we found a significant DR longevity response in three other separate (before unpublished) experiments we previously conducted (p < 0.0001; Table 2). These experiments compared 2% yeast (our standard DR diet) to 8% yeast (the standard ad libitum diet used by our lab) (McCracken, Buckle, et al, 2020) (Figure 1).…”

The importance of reaction norms in dietary restriction and ageing research

“…However, comparisons among these studies are challenging, as effects are often not expressed in comparable manner, i.e. in a relevant effect size such as hazard ratio (Gautrey & Simons, 2022;McCracken, Buckle, et al, 2020).…”

“…By varying carbohydrate and protein content in a geometric framework (Simpson & Raubenheimer, 1993), restriction of dietary protein was suggested as a key determinant of longevity for insects and mice (Piper et al, 2011; Solon-Biet et al, 2014). However, whether dietary protein alone, more specifically amino-acid availability, is directly responsible for DR’s pro-longevity effect has recently been brought into question by experiments in the fly ( Drosophila melanogaster) (Gautrey & Simons, 2022; Zanco et al, 2021). Furthermore, the effects of calories have been suggested to be more important than considered in the geometric framework in mice (Speakman et al, 2016).…”

“…Left largely underappreciated in DR research especially is that single nutrients within this space can interact and could determine longevity in specific circumstances only. Thus, observations of specific nutritional components explaining DR (Gautrey & Simons, 2022; Grandison, Piper, et al, 2009; Zanco et al, 2021) could be relevant in one context only. As such the reaction norm between diet and longevity (Figure 1) should be seen as a concert of different interacting nutrients that shift in importance according to environmental and genetic effects.…”