Genetic Interaction with Temperature in Nematode Longevity

Environmental temperature and longevity tend to be related in species that do not maintain their body temperature. You might look at research into the sizable differences between life spans of various mussel species and how that relates to the temperature of the waters in which they are found, for example. It is an interesting question as to how relevant this research is to mammals, which do regulate their body temperature. While there appears to be a relationship between regulated body temperature and longevity in mammalian species, it is far from clear that this has much in common with the environmental temperature and longevity relationships observed in species such as the nematode worms investigated here. In any case, this, like calorie restriction, is not the road to rejuvenation therapies that will radically alter the present course of aging. Rather, it is the path to a better understanding of how the natural state of aging tends to vary between individuals and species. This is interesting, but not transformative.

As in other poikilotherms, longevity in C. elegans varies inversely with temperature; worms are longer-lived at lower temperatures. While this observation may seem intuitive based on thermodynamics, the molecular and genetic basis for this phenomenon is not well understood. In C. elegans, animals that develop and age at 15 °C ('low temperature') are long-lived compared to wild-type animals grown at 20 °C (room temperature), whereas wild-type worms that develop and age at 25 °C ('high temperature') are short-lived compared to wild-type worms grown at 15 °C or 20 °C. This 'temperature law' has been described as widely accepted, but not tested beyond limited number of strains.

While the 'temperature law' is observed among wild-type organisms, the interplay between genetics and temperature is not well understood. Multiple recent reports suggest that the effects of temperature on longevity are genetically controlled and that both heat and cold modify transcriptional pathways that effect lifespan. To better understand the interplay between temperature and longevity, we measured the lifespans of worms with genetic manipulations known to affect longevity at 15 °C, 20 °C, or 25 °C. We found six examples of how longevity can be impacted across temperatures, representing conditions that: robustly increase lifespan at all temperatures (daf-2 RNAi); robustly decrease lifespan at all temperatures (rhy-1(ok1402)); decrease lifespan at high but not low temperature (daf-16(mu86)); increase lifespan at high temperature but decrease lifespan at low temperature (rsks-1(ok1255)); increase lifespan at low temperature but not high temperature (cep-1(gk138)); and do not alter lifespan at any temperature (cah-4 RNAi).

Having established that relative longevity can vary across temperatures, we next asked whether this variability is common among conditions known to modify longevity. We tested nearly fifty genotypes and interventions previously reported to affect lifespan and found that relative longevity was consistently inconsistent across temperatures. However, there are consistent trends within longevity pathways, where strains/conditions known to have opposing effects are also affected by temperature oppositely. In summary, we find significant interaction between longevity interventions and environmental temperature in two-thirds of the cases examined, indicating that a temperature-independent effect on longevity is more the exception than the rule. This variation confirms that genetics play a substantive role in temperature-dependent longevity that cannot be explained solely by the rules of thermodynamics and chemical kinetics. The observed variation in relative longevity with temperature is consistent with the hypothesis that distinct mechanisms determine nematode longevity at different temperatures.

It has been suggested that protein quality control and the heat stress response are of primary importance for determining nematode longevity at 25 °C. Our data support this model; we find interventions that limit heat stress response (e.g., daf-16(mu86)) are detrimental at high, but not low, temperature, while interventions that improve protein homeostasis, such as dietary restriction or reduced expression of translation machinery (e.g., rsks-1(ok1255), rpl-6 RNAi), show lifespan extension at high temperature. The relevant mechanisms affecting longevity at low temperature are less clear, particularly because relatively few aging studies are conducted at 15 °C compared to 20 °C or 25 °C. Our results demonstrate that the impact of temperature on relative lifespan is of greater importance than generally appreciated by the C. elegans aging field. The vast majority of published studies report the impact of different interventions on lifespan at a single temperature, usually either 20 °C or 25 °C. We suggest that studies reporting effects on lifespan should typically be performed at more than one temperature to understand the robustness of the effect and the interaction with temperature.



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