In a new study, researchers have found that lithocholic acid, a metabolite found in the serum of calorically restricted mice, can mimic the effects of caloric restriction [1].
Restricting calories to live longer
Caloric restriction without malnutrition improves healthspan and extended lifespan in multiple model organisms and has been found to have health benefits in human studies. We have covered the many benefits of caloric restriction on longevity and healthspan, including a recently published interview in which we discussed one of the longest-running caloric restriction experiments on monkeys.
Mimicking caloric restriction
Restricting calories changes many aspects of an organism’s metabolism [2]. One of its well-documented effects is the activation of AMP-activated protein kinase (AMPK). AMPK is an essential regulator of multiple signaling pathways, including aging-related pathways and cellular processes, and mediates many of these beneficial effects [3]. In this study, the researchers used AMPK as a proxy to identify metabolites that mimic caloric restriction.
The researchers subjected mice to 4 months of caloric restriction. Then, they treated a few cell lines with serum from calorically restricted mice. The serum activated AMPK in those cell lines, suggesting that this serum mimicked the effects of caloric restriction. The activation of AMPK was also possible in the liver and muscle cells of normally fed mice treated with the serum of calorically restricted mice.
Finding ‘the one’
Being able to mimic the effects of caloric restriction without restricting caloric intake is an intriguing idea. However, using a whole serum from mice to achieve it is not a practical solution, especially since, most likely, only one or a few molecules from the serum are responsible for the effect of AMPK activation. The researchers went on a quest to identify those molecules.
They employed mass spectrometry-based approaches to identify over a thousand specific metabolites in the serum, and almost seven hundred that were altered by caloric restriction. After performing a few more tests to narrow the list, they performed a screen on cell cultures using AMPK activation as a biomarker.
In the initial screening, the researchers identified six metabolites that increased after caloric restriction and activated AMPK in cell cultures. However, the concentrations needed to activate AMPK by most of those metabolites were too high to be used in physiological conditions.
Only one of the identified metabolites, lithocholic acid (LCA), one of the bile acids (but not its derivatives), activated AMPK when administered at a concentration similar to that in the serum.
Late-life intervention
The researchers asked whether LCA can improve aging-related phenotypes when administered later in life. To test it, they gave aged mice LCA for one month. They noted that while mice and humans differ in their bile acid composition, LCA concentrations are similar in both species [4, 5].
The authors observed many improvements following LCA treatment in mice, including increased running distance, duration, and grip strength, and positive impact on other molecular measures, such as NAD+ levels, mitochondrial content, mitochondrial respiratory function, glucose tolerance, and insulin resistance.
LCA also didn’t cause muscle loss, a phenotype observed in mice and humans when restricting calories [6], suggesting that LCA treatment may be more beneficial. Additionally, muscle regeneration after damage was accelerated in aged mice following the LCA treatment.
Extending lifespan
As AMPK is an essential player in mediating lifespan extension [3], the researchers tested if LCA can mimic the effects of caloric restriction and extend lifespan in the model organisms C. elegans (worms) and D. melanogaster (fruit flies).
LCA treatment in worms and flies activated AMPK and extended their mean lifespans. In hermaphroditic C. elegans, lifespan was extended from 22 to 27 days. Lifespan extension from LCA was similar to that of caloric restriction and consistent with previous reports showing LCA-mediated lifespan extension in flies [7]: from 47 to 52 days in males and from 52 to 56 days in females.
The positive effect of LCA treatment was also evident in healthspan markers in worms and flies, for example, in a few measurements of resistance to different stresses or NAD+ levels. The activity of AMPK was necessary for those improvements since inactivating the AMPK gene in worms or flies abrogated those anti-aging effects.
The effects of LCA were more modest in mice, resulting in “a consistent, albeit nonsignificant, increase in median lifespan” when LCA was started at one year of age. Depending on the cohort, the increase was between 5.1% and 9.6% for male and between 8.3% and 12.5% for female mice.
The authors suggest that altering the LCA dose or the age at which LCA was administered might improve lifespan extension.
The role of gut microbes
The authors point to gut microbes’ role in LCA metabolism. LCA precursors are secreted from the liver to the intestine, where microbes, specifically by Lactobacillus, Clostridium, and Eubacterium species, convert it to LCA. Those microbes are known to be increased after caloric restriction [8, 9].
“It is reasonable to suggest that the LCA increase that occurs during CR may be caused by changes in these gut microbes.” Current and previous research supports the role of gut microbes in LCA metabolism when calories are restricted. The authors report detecting higher concentrations of LCA in the feces of calorically restricted mice. This was not observed in mice lacking gut microbes or with disrupted gut microbiome due to antibiotic treatment. Similarly, transplanting feces from calorically restricted mice into germ-free mice or antibiotic-treated mice caused an increase in LCA levels, which was higher than when feces were transplanted from normally fed mice.
The role of Clostridioides in increasing LCA levels is also supported by human research, as healthy centenarians with high Clostridioides levels also have high levels of LCA [10].
The authors summarize that their research “provided multiple lines of evidence to show that LCA acts as a CRM [caloric restriction mimetic], recapitulating the effects of CR, including AMPK activation and rejuvenating and anti-aging effects.“
While their research was conducted on model systems, they point to a previous study that observed that LCA was observed to be increased in the serum of healthy humans following 36 hours of fasting, suggesting a link between LCA and fasting in humans [11].
Literature
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