A new review maps how specific amino acids shape metabolism and cellular aging while explaining why laboratory promise is not yet ready to guide dietary advice.

Review: The hallmarks of protein and amino acid restriction in aging and longevity. Image Credit: Christoph Burgstedt / Shutterstock

A recent review published in the journal Cell Press Blue suggests that restricting specific amino acids may reproduce some of the metabolic benefits of protein restriction (PR), as observed mainly in experimental models, with potential implications for overall health and longevity.

The findings raise questions about current health recommendations to increase protein intake for older adults, but do not establish that older adults should reduce specific amino acids to extend healthspan or lifespan.

Increasing protein consumption is a widely promoted health recommendation. Interestingly, researchers are now finding that protein restriction could improve metabolic health and longevity in laboratory organisms, while short-term human studies indicate possible metabolic benefits.

In particular, animal studies restricting dietary intake of amino acids such as isoleucine, methionine, and valine have demonstrated many of the health benefits of PR, highlighting that the amino acid composition of dietary protein may determine health outcomes related to aging.

As protein-fortified foods increasingly appear on supermarket shelves, it is crucial to understand which type of protein, and in what amounts, may be beneficial for healthy aging.

In this review, researchers discuss how restricting specific amino acids influences nutrient sensing, metabolism, mitochondrial function, the epigenome, and senescence, drawing on evidence from humans, laboratory animals, cells, and organisms such as yeast, worms, and fruit flies.

Protein Restriction and Related Evidence

The official Recommended Dietary Allowance is 0.8 grams of protein per kilogram of body weight daily for adults, regardless of age, whereas expert groups routinely recommend 1.0 to 1.2 grams per kilogram for adults aged 65 years or older.

In short-term studies, individuals consuming high-protein diets experienced greater weight loss than their peers, likely due to improved satiety and reduced food intake, particularly among highly compliant participants. When combined with adequate protein intake, resistance exercise may help older adults preserve muscle function and reduce age-related frailty.

Nevertheless, high protein intake has also been associated with an increased likelihood of diabetes, cancer, overall mortality, and cardiovascular mortality. Similar associations have been observed among participants in the National Health and Nutrition Examination Survey (NHANES), although observational studies cannot establish causation, and the associations may vary by age and protein source.

Consistent with preclinical findings, short-term randomized controlled trials (RCTs) are increasingly demonstrating that low-protein diets can lower blood glucose levels and body weight without calorie restriction and, in one study, even with increased calorie intake.

Limiting the intake of certain amino acids can also improve insulin responsiveness in short human studies. Increased energy expenditure has been reported during protein restriction in lean men and in experimental models, while a 4-week branched-chain amino acid (BCAA) restriction trial improved glucose and insulin homeostasis in people with metabolic syndrome.

Hallmarks of Protein Restriction and Underlying Mechanisms

In animal models, dietary PR can reduce adiposity and improve longevity by increasing energy expenditure while also improving glucose homeostasis. These effects are partly associated with increased fibroblast growth factor 21 (FGF21) expression following restriction of dietary protein, methionine, isoleucine, sulfur amino acids, or combined branched-chain amino acids (BCAAs). In animal models, FGF21 helps tissues use glucose to generate energy and heat and can increase sympathetic activity.

Experimental evidence also links FGF21 to increased insulin sensitivity and fatty acid uptake in adipocytes, along with lower blood triglyceride levels and reduced inflammation in renal and hepatic tissues. Using mouse models, researchers found that FGF21 overexpression extended lifespan, while its expression in the thymus and adipose tissue slowed some age-related immunological changes.

By reducing dietary BCAAs by 60-75% for 7 days to 4 weeks, two short human studies reported improved insulin sensitivity and glucose and insulin homeostasis. The four-week intervention also raised circulating FGF21, whereas the cognitive benefits of BCAA restriction have been reported only in rodent models.

In the four-week human trial, BCAA restriction reduced mechanistic target of rapamycin complex 1 (mTORC1) signaling in white adipose tissue. Reduced hepatic mTORC1 activity and cellular senescence have been observed in rodents and may also contribute to these beneficial effects.

Experimental restriction or depletion of arginine, asparagine, and tyrosine has affected general control nonderepressible 2 (GCN2), or mTORC1 signaling in cells, yeast, and fruit flies, but the dietary benefits in humans remain unknown. By activating GCN2, PR can promote the translation of activating transcription factor 4 (ATF4) to mediate autophagy and stress responses. Evidence for lysine restriction is currently limited to reduced obesity in mice.

Separate studies of broader protein restriction have reported reduced adipose and liver senescence, reduced hepatic reactive oxygen species (ROS), and increased mitochondrial activity, primarily in laboratory models.

Experimental methionine restriction may alter histone methylation and gene expression by changing the availability of methyl donors. Strict vegan diets have been associated with lower circulating methionine and favorable metabolic outcomes, but whether these diets preserve a more youthful human epigenome remains unknown.

Researchers have hypothesized that Okinawan Japanese people live longer than others due to their dietary choices, with their traditional diet containing approximately nine percent protein and deriving approximately 80% of its calories from plant sources, which resembles PR diets commonly used in laboratory investigations. However, Okinawans also traditionally consumed fewer calories overall, making it difficult to attribute their longevity specifically to lower protein intake.

These observations support the possibility that PR may promote healthy aging in humans, but do not establish that lower protein intake or plant protein was responsible for the population’s longevity. In Drosophila, researchers observed that PR improved cellular resilience to stress and infection. This finding needs to be confirmed in mammals to determine whether these resilience effects extend beyond insects.

Implications

The findings highlight the potential benefits of limiting the intake of certain amino acids for healthier aging, although much of the longevity evidence currently comes from laboratory models. This approach may eventually be a viable alternative to sustained calorie restriction for improving cardiometabolic health.

Consuming certain proteins may help keep people full for longer, while restricting specific amino acids may improve aspects of glucose and lipid metabolism, but this combined dietary strategy has not been directly tested. 

Conversely, some studies have associated higher BCAA intake with a lower risk of sarcopenia or found that BCAA supplementation combined with light resistance exercise improved muscle strength in older people, indicating that the evidence remains incomplete.

In future studies, researchers could clarify the effects of restricting individual amino acids on biological mechanisms related to mitochondrial function and cellular resilience in humans, while identifying safe restriction levels and accounting for age, sex, physical activity, nutritional status, and health conditions.

Protein or amino acid restriction could be harmful for pregnant women, growing children, people recovering from injuries, individuals consuming insufficient calories, and older adults who already have inadequate protein intake. The effects of PR on human lifespan remain unknown.

Note: D. W. Lamming has received funding from and serves on the scientific advisory board of Aeovian Pharmaceuticals, which is developing selective mTOR inhibitors.