Calorie restriction promotes longevity, as many studies have shown. Now, if only we could restrict our caloric intake by implementing a quick mechanical fix, such as narrowing the neck that connects an hourglass’s two bulbs, then we might extend our lives without having to demonstrate a superhuman degree of temperance. Could such a fix be possible at the molecular level? The question has motivated a search for calorie-restriction mimetics (CRMs), molecules that induce the sorts of metabolic changes that result from actual calorie restriction.

Two recent studies mark progress toward two very different CRMs. One of the studies, from the Institut Pasteur, focuses on GDF11, a protein best known for playing various roles in embryonic development. According to Institut Pasteur researchers, GDF11 appears to be a link between calorie restriction and the rejuvenating effects of young blood.

The other study, from the French Medical Research Council (INSERM), suggests that 3,4-dimethoxy chalcone (3,4-DC), a polyphenol, may emulate the calorie-restriction-mimetic ways of similar polyphenols, namely, spermidine and resveratrol. These molecules appear to promote autophagy, a rejuvenating process that occurs at the cellular level. Autophagy, or self-eating, allows the orderly elimination of toxic and misfolded proteins.

Although GDF11, which belongs to the Growth Differentiation Factor protein family, has been shown to reduce cardiovascular disease, prevent cancer, and increase neurogenesis in the brain, scientists haven’t been sure of its efficacy in slowing aging. They’ve been holding out for evidence that GDF11 contributes to an age-delaying mechanism, such as one associated with calorie restriction.

In search of such a mechanism, scientists at the Institut Pasteur’s Perception and Memory Unit led by Pierre-Marie Lledo, PhD, decided to establish GDF11’s organ-rejuvenating mechanisms, and then evaluate whether they might overlap with the protein’s calorie-restriction-mimetic mechanisms. Specifically, the scientists followed up on previous research that injecting aged mice with blood from young mice rejuvenated blood vessels in the brain, and consequently improved cerebral blood flow, while increasing neurogenesis and cognition.

The results of the new work appeared October 22 in Aging Cell, in an article titled, “Systemic GDF11 stimulates the secretion of adiponectin and induces a calorie-restriction‐like phenotype in aged mice.”

“Systemic GDF11 triggers a calorie-restriction‐like phenotype without affecting appetite, restores the insulin/IGF‐1 signaling pathway, and stimulates adiponectin secretion from white adipose tissue by direct action on adipocytes, while repairing neurogenesis in the aged brain,” the article’s authors wrote. “These findings suggest that GDF11 has a pleiotropic effect on an organismal level and that it could be a linking mechanism of rejuvenation between heterochronic parabiosis and calorie restriction.”

Adiponectin is a hormone that induces weight loss without affecting appetite. In animals that have undergone calorie restriction, the blood levels of this hormone are high. “In animals that were administered GDF11, we also observed high levels of adiponectin,” said Lida Katsimpardi, “and this shows that GDF11 causes metabolic changes similar to those induced by calorie restriction.”

“These findings are encouraging,” added Lledo, “and they support therapeutic uses of GDF11 in certain metabolic diseases, such as obesity, and neurodegenerative diseases.”

Left: Neurogenesis induced by GDF11 supplementation in aged blood. Right: Absence of neurogenesis with aged blood. [Institut Pasteur]

In the other study, the one from the French Research Council, the scientists also decided to follow up on previous research. In this case, however, the research or interest concerned the autophagy-promoting effects of the CRMs spermidine and resveratrol. The French Research Council scientists, led by Guido Kroemer, PhD, director of the apoptosis, cancer, and immunity research team, were aware that the anti-aging effect of these CRMs had been demonstrated in a variety of species from yeast to worms and on to mice. In addition, spermidine had been correlated with human longevity and reduced cardiovascular and cancer-related mortality.

To uncover more CRMs, Kroemer and his team tested 200 compounds that belong to the same class of substances as spermidine and resveratrol. They first examined which of these substances show cellular reactions characteristic of elevated autophagy in rat and human cell cultures, while not being toxic to the cells. An agent called 3,4-dimethoxy chalcone (3,4-DC) stood out as the best candidate.

Additional details appeared October 14 in EMBO Molecular Medicine, in an article titled, “3,4‐Dimethoxychalcone induces autophagy through activation of the transcription factors TFE3 and TFEB.”

“When added to several different human cell lines, 3,4‐DC induced the deacetylation of cytoplasmic proteins and stimulated autophagic flux,” the article’s authors wrote. “[Like] other well‐characterized CRMs, 3,4‐DC [leads to autophagy, but it does so via a different pathway, one requiring] transcription factor EB (TFEB)‐ and E3 (TFE3)‐dependent gene transcription and mRNA translation.”

The researchers then investigated the effect of 3,4-DC on living animals. To this end, they injected the substance into mice. They found that it protects against myocardial infarction and that it reduces the growth of tumors in the context of certain chemotherapeutic agents. Both effects have previously been associated with autophagy and with CRMs such as spermidine and resveratrol.

It remains to be seen whether 3,4-DC has similar effects in humans. However, the study is a proof of principle that the researchers’ approach to testing substances in cell culture is a fast and efficient way to identify new CRM candidates with diverse modes of action.

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