Researchers provide framework for studying precision nutrigeroscience

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Dietary restriction is arguably the most promising non-genetic method for extending the lifespan and lifespan of many model organisms, including mammals. As researchers scramble to develop interventions that mimic the benefits of dietary restrictions in humans (who typically struggle to maintain a Spartan diet), the lab work of Prof. Buck Pankaj Kapahi, PhD, suggests that the benefits of dietary restrictions often vary. between individuals and even in the tissues within those individuals. He and his colleagues are challenging the field to change their approach to dietary restriction and aim for specific and individualized interventions. In a review Posted in Cell metabolism, they provide a framework for a subspecialty called precision nutrigeroscience, based on biomarkers affected by genetics, gender, tissue and age.

“Everyone’s hoping for a ‘one-size-fits-all’ diet intervention, and work in our lab and several others shows that just won’t be the case,” says Kapahi, whose team aims to understand the mechanisms. whereby nutrient signaling and metabolism influence aging and age-related diseases. “I had to change the way I think about aging. Many of us go very deep into the details of understanding what I call two-dimensional biological pathways, and we forget a whole other dimension which is that these pathways are different in each individual and in the tissues of individual bodies. Context matters and we cannot make real progress in this area without including it. We will end up harming the ground because the interventions will end up not working and people will be disappointed. “

Studies on genetically distinct strains of fruit flies have shown the need for precision nutrition

In 2020, postdoctoral fellow Buck Kenneth Wilson, PhD, who is the first author of this review, performed a genome-wide analysis of 160 genetically distinct strains of the fruit fly. Drosophila melanogaster who ate the same Spartan diet. Publication in Current biology, he and his team showed that lifespan and lifespan were unrelated under dietary restriction. While 97 percent of the strains showed some extension in lifespan or health with the limited diet, only 50 percent showed a significantly positive response to food restriction for both. Thirteen percent of the strains were more vigorous, but died sooner due to dietary restriction; 5% lived longer but spent more time in poor health. The remaining 32 percent of the strains showed no benefit or harm to lifespan or health duration, or negative responses to both.

“I think it’s important that everyone in the field understands and appreciates that there are many different ways of looking at what an intervention might do. You might see an answer in one case, but that answer might not work in another strain of the same species, ”Wilson explains. “Conversely, if you can’t see anything, it doesn’t mean that the intervention you are testing isn’t working, it just means that you are not using the right model for that intervention. Wilson says it’s also crucial for researchers to be aware of the possible disconnect between lifespan lengthening and lifespan when it comes to diet. “I think the last thing any of us wants to do is give people more years of poor health.”

What the exam includes

The review provides a detailed introduction covering several forms of dietary restriction (from calorie restriction to various forms of intermittent fasting as well as diets that restrict proteins, carbohydrates, specific amino acids, micronutrients and metabolites) and details the effects. associated in yeasts, worms, flies and mice. Researchers explain the mechanisms for detecting nutrients such as IGF-1, TOR and AMPK-like signaling. They discuss regulators of metabolic reprogramming, including sirtuins and NAD, as well as regulators of the circadian clock. They include the mediating effects of fat and lipid metabolism, proteostasis and autophagy, and reduction of cell senescence as well as mitochondrial function.

The authors cover the complexities of measuring aging in response to food restriction, explaining how lifespan analysis is used to decipher the mechanisms of food restriction, possible gene-specific lifespan responses to dietary interventions and the role of sex in species that have males. and females. The authors also cover the effects and molecular drivers of dietary restriction on disease patterns in simple animals and mammals, including diabetes, cardiovascular disease, kidney disease, cancer, and neurodegenerative disease. They also provide insight into the debate between measuring lifespan and health and summarize molecular biomarkers of aging that have been used in studies of dietary restriction.

“We want to give scientists entering the field of research on aging some insight so that they can start separating forest from trees when it comes to dietary restriction,” says Kapahi. “We also wanted to discuss the utility of understanding exceptions to the current paradigm whereby dietary restriction is beneficial at all levels in all species studied while providing light at the end of the tunnel. We know the science is complex, but if we can frame dietary restriction in the context of precision medicine, everything people learn in the field will apply to the larger effort of improving and expanding. human health. The bottom line is that there is no such thing as “negative” or “positive” data – we can learn from it and it will take a big team effort to fully develop Precision Nutrigeroscience.

For better (and for worse): what we know about humans and dietary restrictions

The review also includes data on the reported effects of dietary restriction in humans. While current data shows that dietary restriction has positive effects on neurodegeneration, diabetes, cardiovascular disease, and kidney disease, the authors report that there are indications that restricting the food we eat may reduce density. bone mineral, resulting in osteoporosis.

Researchers say that when it comes to normal aging, dietary restriction likely has broad benefits in many physiological systems, but data shows that restrictive diets negatively limit wound healing and could impact our ability to survive. recover from fractures. While muscle preservation is upregulated by dietary restriction, data also shows that muscle growth is inhibited. The authors say that exercise could improve these deficits, adding another factor that must be taken into account when studying the effects of food restriction. And while the data shows that respiratory function improves with food restriction, it also shows that exercise capacity may decrease at the same time.

“The age of the person using a dietary restriction is also a factor that needs to be investigated and taken into account,” explains Wilson. “It has been shown that older people may not want to limit their food intake, especially when it comes to protein that helps maintain muscle mass.”

What about the genre?

Kapahi says gender is one of the main factors leading to variable responses to food restriction, repeating a little-known but relevant adage: “When it comes to DNA, human males have more in common with the male chimpanzee than it does. ‘with human females. ” He adds that in flies and mice, females are much more sensitive to dietary changes than their male counterparts, possibly due to physiological effects on the female reproductive system and its interaction with other systems. He also points out that until recently, most studies in mice and humans disproportionately involved males.

Women are at greater risk of developing Alzheimer’s disease. Two-thirds of Americans living with memory disease are women, and experts say that figure can’t be explained by the fact that women tend to outlive men. Wilson, who now studies neurodegeneration in flies, mice, and human cell cultures, says diet may one day come into play. “Diet has been shown to improve neuronal function,” he says. . “We’re not sure all of the mechanisms involved in this, but the link between sex and food restriction will be part of the plan.”

Implications for clinical trials and potential interventions

Kapahi says taking an individualized approach to dietary restriction could result in more focused and informative clinical trials, as researchers could identify and recruit subsets of people more likely to respond to a particular intervention. “There is a good chance that we will be able to increase the number of potential interventions as well,” he says. “There are probably effective therapies that already exist that have been ruled out because they have not been well tested in a particular strain or species of model organism. There is a real benefit in giving up the search for a “one size fits all” / “magic pill” solution to the physical problems of aging. ”

Kapahi expects more studies and conferences focused on Precision-Nutrigeroscience will help the field grow.

– This press release was originally published on the Buck Institute for Research on Aging website


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