The importance of reaction norms in dietary restriction and ageing research

Abstract

Ageing research has progressed rapidly through our ability to modulate the ageing process. Pharmacological and dietary treatments can increase lifespan and have been instrumental in our understanding of the mechanisms of ageing. Recently, several studies have reported genetic variance in response to these anti-ageing interventions, questioning their universal application and making a case for personalised medicine in our field. As an extension of these findings the response to dietary restriction was found to not be repeatable when the same genetic mouse lines were retested. We show here that this effect is more widespread with the response to dietary restriction also showing low repeatability across genetic lines in the fly (Drosophila melanogaster). We further argue that variation in reaction norms, the relationship between dose and response, can explain such conflicting findings in our field. We simulate genetic variance in reaction norms and show that such variation can: 1) lead to over- or under-estimation of treatment responses, 2) dampen the response measured if a genetically heterogeneous population is studied, and 3) illustrate that genotype-by-dose-by-environment interactions can lead to low repeatability of DR and potentially other anti-ageing interventions. We suggest that putting experimental biology and personalised geroscience in a reaction norm framework will aid progress in ageing research.

Dietary restriction extends lifespan across different temperatures in the fly

“… Note : Log hazard estimates (logHR, with their standard error, SE) reported from separate models for each experiment as we found slight differences in the response to DR across these experiments, which is expected even in replication due to small variations in unknown experimental factors (Simons & Dobson, 2023). …”

“…Cooked fly media was stored for up to 2 weeks at 4–6°C, and warmed to 25°C before use. For all experimental diets (to which no propanoic acid was added), all components of the fly food media remained consistent but the amount of yeast was varied (2%, 4%, 6%, 8% and 10% yeast), representing a spectrum of rich to restricted diets (McCracken, Buckle, et al., 2020; Simons & Dobson, 2023). For experimental diets, 8% yeast is the standard ad libitum diet used by the laboratory and 2% is the standard restricted diet used.…”

“…We recently argued that an absence of a DR response can be due to shift in reaction norm rather than a change in the dose–response (Simons & Dobson, 2023). Although this point has been made by us and others (Flatt, 2014; Tatar, 2011) misinterpretations are still made.…”

“…These interactions can also be more complicated with environmental conditions increasing the requirement of a key nutrient that is in short supply in the DR diet, leading to a truncation of lifespan, even though the restriction of this key nutrient is not causal in the DR longevity phenotype. Careful consideration of a range of diets can thus be crucial when concluding environmental or genetic conditions negate the DR response (Simons & Dobson, 2023).…”

“…We use substantially larger sample sizes per treatment group ( N is between 253 and 505 females) compared to the work that led to this hypothesis ( N = 100) (Zajitschek et al., 2023). We further used a broad range of five diets to be able to distinguish a shift from a change in shape of the DR lifespan reaction norm (Simons & Dobson, 2023).…”