Fewer Calories, Better Cell Performance

Calorie restriction, reducing calorie intake by 40% or so while maintaining optimal micronutrient intake, is the most reliable way to upregulate all of the cellular maintenance processes that act to improve cell and tissue function. This response to famine evolved very early on in the history of life on our planet, and near all organisms assessed by the research community have a cellular metabolism that operates more efficiently when calories intake is restricted. While everyone should consider trying calorie restriction, given the health benefits it conveys, and given that it costs nothing, it isn't the path to a sizable extension of life span in our species. Efforts to recreate even thin slices of the metabolic response to calorie restriction have proven to be challenging, despite an investment of billions and decades, and even the best present development programs achieve little in the grand scheme of what might be possible given better approaches to the problem of aging. They will only modestly slow aging, not radically change the length of human life.

The number of calories a person eats directly influences the performance of different cells. One experiment on mice shows how a low calorie diet can protect the brain from neuronal cell death associated with diseases such as Alzheimer's, Parkinson's, epilepsy, and cerebral vascular accident (CVA). The mice were divided into two groups. The researchers calculated the average number of calories the group with no caloric restrictions would eat and then fed the other group 40% fewer calories. After 14 weeks, mice belonging to the two groups were given an injection containing a substance known to cause seizures, damage, and neuronal cell death.

While the animals in the group that had no dietary restrictions had seizures, the animals whose calories had been restricted did not. The researchers then studied what occurred in vitro. To do that, they isolated the organelles called mitochondria of the brain cells of the mice, which were also divided into two groups: those that had unrestricted diets and those that had restricted diets. When calcium was introduced to the medium, they noted that uptake was greater in the mitochondria belonging to the group that had ingested fewer calories. Mitochondria are the organelles responsible for energy generation in cells. In the case of the mice subjected to a calorie restricted diet, mitochondria increased the calcium uptake capacity in situations where the level of that mineral was pathologically high.

In the pancreas, caloric restriction has shown to be capable of improving cell response to increased levels of blood glucose. The researchers reached this conclusion after conducting experiments using beta cells that remain in the pancreatic islets and are responsible for producing insulin. Blood serum from mice subjected to a variety of diets, similar to the study on the effects of caloric restriction on neurons, was used to nourish the cells cultivated in vitro. In the cells treated with the serum of animals that ate fewer calories, insulin secretion through the beta cells occurred normally: low when glucose was low and high when glucose was elevated. This did not occur in the animals that ate more calories (and became obese). The experiment showed that there may be a circulating blood factor that acutely modifies beta cell function.

Researchers have again raised the hypothesis of whether the phenomenon is related to the mitochondria, since insulin secretion depends on the availability of ATP (adenosine triphosphate, the molecule that stores energy) in the cell. When they measured oxygen consumption by the two groups of cells, they observed that it was higher in cells that received serum from animals subjected to caloric restriction. Since respiration is responsible for the release of insulin during peak glucose, it was a sign that the cells generated more ATP under that condition. Other experiments have also shown that the mitochondria of cells treated with serum from animals subjected to caloric restriction exchanged more material with each other, which made them more efficient.

Link: http://fapesp.br/week2019/london/news/diets-consisting-of-fewer-calories-improve-cell-performance

Comments

Billions have not been spent on CR mimetics. Sirtris is the only company explicitly targeting CR via sirtuin activation. That failed for business reasons, not scientific ones. Sirtuin activation is legit -- the Sirtris compounds may not have been (although GSK has not disclosed the situation, 10 years later). And there are more ways to chemically induce CR than sirtuin activation per se.

Caloric restriction is still the best ***proven*** geroprotective intervention and we do not yet have an effective, safe CR mimetic. Autophagy enhancement is even better supported by the evidence than senescent cell ablation. Here are some examples:

Overexpression of Atg5 in mice activates autophagy and extends lifespan.
https://www.nature.com/articles/ncomms3300

Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice
https://www.nature.com/articles/s41586-018-0162-7

Essential role for autophagy in life span extension
Frank Madeo,1,2 Andreas Zimmermann,1 Maria Chiara Maiuri,3,4 and Guido Kroemer3,4,5,6

https://www.jci.org/articles/view/73946

The life extension from more radical interventions involving gene and cell therapy remains largely theoretical. Of course we should pursue them, but we should not make the perfect become the enemy of the good.

We need to get the lowest hanging fruit of geroscience to the market. Once one or two geroprotectors are on the market, the flood gates will open.

Posted by: Sebastian Aguiar at March 17th, 2019 12:30 PM

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