Caloric restriction, longevity and aging: Recent contributions from human and non-human primate studies

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Calorie restriction, an efficient strategy to increase longevity

Caloric restriction (CR), consists in reducing calorie availability by up to 50%. It is one of the rare non genetic strategies that extends lifespan.While CR might be a very efficient anti-aging strategy, its definition and limits must be well understood before envisaging to apply it to human.

In this review, we first report and compare the recently issued CR studies in non-human primates (focusing on longevity studies) and humans and then try to understand what an optimal caloric intake is. One of the goal of the present mini-review is to address the pertinence of using CR as an anti-aging strategy with respect to the risks of frailty and obesity, what we discuss in a last part.

In short-lived species such as rodents, CR can increase maximal lifespan up to 50% (McCay et al., 1935) while improving general health and decreasing aging-associated diseases (Fontana et al., 2010). CR reduces the onset of several diseases, among which atherosclerosis, cancers, diabetes, renal, neurodegenerative and respiratory diseases (for review see (Fontana et al., 2010; Chung et al., 2013; Fontana et al., 2018)).

Beneficial effects of CR on age-related diseases have also been reported for long-lived species including rhesus monkeys (Macaca mulatta) at the Wisconsin National Primate Research Center (Colman et al., 2009; Colman et al., 2014) and at the National Institute on Aging (Mattison et al., 2012). Increased survival was however only reported in the Wisconsin National Primate Research Center study (Colman et al., 2009; Colman et al., 2014; Mattison et al., 2017) while the National Institute on Aging study detected no significant survival effect.

Direct comparison of data from both studies suggested that differences in outcomes of the two studies may have been due to study design differences including the age of CR onset, feeding regimen, diet composition, and genetics (Mattison et al., 2017; Vaughan et al., 2018). Alternatively to studies in macaques, the effects of CR were recently demonstrated on the health and lifespan of the grey mouse lemur (Microcebus murinus), a small lemurid primate originating from Madagascar.

With a median survival in captivity of 5.7 years for males and maximum lifespan of 12 years (Languille et al., 2012), mouse lemurs represent an emerging promising model for human aging (Bons et al., 2006; Austad and Fischer, 2011; Ezran et al., 2017). They display agerelated alterations of their sensorial system, motor functions, biological rhythms, immune and endocrine systems (Languille et al., 2012).

In this species, aging leads to increased prevalence of diseases such as neoplasia or sarcopenia  and glucoregulatory function alterations (Djelti et al., 2016) that also increase with aging in humans. Finally, their cerebral aging profile is similar to that of humans as they display age-related cognitive alterations associated to cerebral atrophy (Picq et al., 2012a) as well as Alzheimer’s disease-like amyloid lesions (Mestre-Francs et al., 2000).

Better defining the optimal caloric intake?

So far, most of CR studies, from yeasts to non-human primates, come to the same conclusion: CR is an efficient strategy to increase healthspan and lifespan. However, a fundamental question is still not answered: what is the nutritional status of CTL animals compared to CR animals? Are control animals receiving optimal caloric intake or are they generally overfed and thus metabolically morbid, as proposed by Martin and colleagues (Martin et al., 2010)? The question deserves to be addressed. Determining the optimal caloric intake for a given species is difficult, mainly because it depends mainly on the level of locomotor activity. In this context, it is possible to compare the body weight of laboratory bred animals to wild conspecifics.

In the case of mouse lemurs, the mean body weight of the CTL group was between 90 and 110 g, while those under CR were comprised between 60 and 80 g19 (both measures concern summer-acclimated animals, mouse lemur exhibiting physiologic seasonal body weight variations). In comparison, wild animals during the same season weigh around 60 g according to field studies (Schmid and Speakman, 2000; Schmid and Speakman, 2009).

Even if longevity of wild animals is much shorter than animals bred in captivity, they are supposed to receive the correct amount of food, corresponding to their needs and the environment in which they evolved and are thus adapted for. In addition, field animals are very active in comparison to laboratory animals (the home range of a wild male is comprised between 1 and 2.5 ha) (Radespiel, 2000).

Taking into account that CR lemurs perform 25% more spontaneous locomotor activity (Dal-Pan et al., 2011a) (a phenomenon called food-anticipatory behavior (Caba and Mendoza, 2018; Challet, 2013)), CR animals are much closer to wild animals in term of body weight and activity than CTL. CTL animals could thus be considered overfed (and also probably sedentary), both conditions being deleterious for their longevity.

From that point of view, mouse lemurs bred in captivity can be considered as a good model of modern human. Data from Redman and colleagues, (the 2 years CR human study (Redman et al., 2018)), tell us that before CR, both experimental groups exhibited a body mass index (BMI) over Such BMI corresponds to an overweight status according to the World Health Organization (WHO, 2018) definition.

Caloric restriction and aging: juggling with the risk of frailty and obesity

The vast majority of studies on CR in humans describe beneficial health effects (recently summarized in a review by Most and colleagues (Most et al., 2017)). However, CR is also worrying gerontologists.

It is true that it can be risky to simply declare that CR is good for all, and Lebourg and Redman perfectly highlighted the risks of simple translation of animals data to humans (Le Bourg and Redman, 2018). Caloric intake should depend on a long list of parameters on top of which are activity level, physical condition and age. The frailty of a given individual should thus be taken into account.

The concept of frailty can be defined as “a reduced physiological reserve with aging, leading to a lower resistance to stressors, frail elderly being at higher risk for adverse health events, disability and death” (Féart, 2018). Since unintentional weight loss is part of Fried’s items criteria (a scale defining the frailty status), CR can lead to increased risk for frailty.

According to Fried and colleagues (Fried et al., 2001), the unintentional weight loss is a marker of frailty susceptibility, thus nutritional status is an important criteria in defining frailty. As a consequence, malnutrition is commonly observed in frail people (Lorenzo-López et al., 2017). Even if frailty and malnutrition are clearly distinct phenomenon, 90% of older people in situation of malnutrition are considered frail (Féart, 2018).

In the general population of older adults (> 65 y.o.), prevalence of frailty is about 10% (Collard et al., 2012). In this specific population, it is obvious that CR should not be considered as a potential intervention. In addition, to our knowledge, there are no studies supporting a beneficial impact of long-term CR in aged animals or individuals.

This said, the risk of frailty must be considered at the light of the prevalence of obesity and obesity-related mortality. Excess weight is clearly a worldwide growing public health concern (including in undeveloped countries) (, n.d.-c). The prevalence of obesity in the adult population in 2017 was over 35% in the U.S. and 15% in France (Collard et al., 2012) and it keeps increasing (NCD Risk Factor Collaboration (NCD RisC), 2016).

A huge number of studies have found an excess risk of death of obese individuals compared to normal-weight adults, obesity being associated with diseases of the circulatory system, diabetes, kidney diseases, and respiratory infections, as well as with cancers of several sites (see (Jura and Kozak, 2016; Avram et al., 2005) for review). Both obesity and aging are conditions leading to increased risk for disease and death.

Aging is associated with an increase in abdominal obesity, a major contributor to insulin resistance and metabolic syndrome. Obesity in the elderly is thus also a serious concern and impairs life quality and expectancy. In a study conducted in four European countries (Stenholm et al., 2017), in people aged between 50 and 75 years, the proportion of life spent in good perceived health was 81% in normal weight people vs 53% in the BMI > 35 category. The proportion of life without chronic diseases was around 65% in normal weight people and 35% in the BMI > 35 category.

Author: Fabien Pifferi, Fabienne Aujard