Protein and Healthy Aging: Could Less Be More?

 Protein restriction, rather than higher-protein intake, could improve metabolic health in older adults and extend both healthy life expectancy and overall lifespan. This is the conclusion reached by Bailey Knopf, researcher, and Dudley Lamming, PhD, from the University of Wisconsin-Madison, in Cell Press Blue. In their review, the researchers examined published studies on protein restriction and identified six effects of reduced protein intake, along with the molecular mechanisms that may promote healthy aging. These benefits appear to be driven primarily by the restriction of specific amino acids, particularly methionine, leucine, isoleucine, and valine.

More or Less Protein?

Current guidelines, such as those from the German Nutrition Society, recommend a daily protein intake of 1.0 g/kg of body weight for adults aged 65 years or older, partly to reduce the risk for sarcopenia and frailty.

However, these recommendations contrast with epidemiologic findings. “Human association studies have found that high-protein diets are associated with an increased risk of diabetes, cancer, and mortality,” the authors wrote.

An analysis of data from the US National Health and Nutrition Examination Survey found that higher-protein intake was associated with increased mortality and age-associated diseases. A 2023 British twin study also found that higher-protein intake was positively associated with sarcopenia among older twins, challenging the conventional view that dietary protein prevents sarcopenia.

On the basis of these findings, Knopf and Lamming examined the potential benefits of reducing total protein intake while still meeting nutritional requirements, as well as the mechanisms that could explain these effects.

Six Key Effects

The researchers identified six major effects of protein restriction that may influence aging and age-associated diseases:

• Improved metabolic health
• Improved nutrient-sensing pathways (metabolic pathways that maintain the balance between energy production, storage, and consumption)
• Reduced cellular senescence
• Improved mitochondrial function
• Favorable epigenetic modifications
• Healthy aging

Effect 1: Improved Metabolic Health

Protein restriction improves metabolic function by reducing excess body weight, increasing energy expenditure, and improving glucose homeostasis. The authors noted that this effect was not caused by reduced calorie intake. Protein restriction can increase food intake while reducing fat mass and body weight because of increased energy expenditure.

Fibroblast growth factor 21 (FGF21), a hormone induced by nutrient stress, appears to be the primary mediator. FGF21 promotes energy expenditure and fat breakdown, increases insulin sensitivity, and exerts anti-inflammatory effects through several pathways.

Effect 2: Improved Nutrient Sensing

Protein restriction activates general control nonderepressible 2, an enzyme that detects amino acid deficiencies and suppresses protein synthesis. At the same time, the production of activating transcription factor 4 (ATF4) increases. ATF4 is a key regulator of the cellular stress response and promotes amino acid synthesis, autophagy, and antioxidant production.

Protein restriction also inhibits the mechanistic target of rapamycin complex 1 (mTORC1), a central protein complex involved in cell growth, energy metabolism, and protein synthesis. Inhibition of mTORC1 further reduces protein synthesis and activates autophagy.

Effect 3: Reduced Senescence

Cellular senescence is the irreversible arrest of the cell cycle. Senescent cells develop a senescence-associated secretory phenotype (SASP), activating proinflammatory signaling pathways that can contribute to tissue dysfunction and accelerate aging. Conversely, eliminating senescent cells may alleviate age-associated diseases.

High-protein diets increase senescence in the liver, whereas protein restriction reduces it. Studies have shown that FGF21 suppresses senescence in cultured cells and reduces the expression of proinflammatory SASP markers. Therefore, reducing senescent cells in metabolic tissues may contribute to the health benefits of protein restriction.

Effect 4: Improved Mitochondrial Function

Mitochondria become less efficient with age and produce more reactive oxygen species (ROS), which can damage cells, cause oxidative stress, and promote senescence. In the liver, ROS contribute to inflammation, fatty liver disease, fibrosis, and cancer. Mitochondrial dysfunction has also been associated with several age-associated diseases, including insulin resistance and type 2 diabetes. Protein restriction reduces ROS levels in the liver.

Studies in mice have shown that a high-protein diet significantly reduces electron transport chain activity in skeletal muscle and impairs exercise endurance. These findings suggest that high-protein intake could adversely affect mitochondrial homeostasis in skeletal muscle.

However, findings on the relationship between dietary protein content and mitochondrial function are inconsistent, and the authors noted that further research is needed.

Effect 5: Positive Epigenetic Modifications

Epigenetic modifications, including DNA methylation and posttranslational modifications of histones, influence which genes are active within a cell. Research suggests that protein restriction may promote a healthy lifespan by regulating the epigenome and preserving or restoring a more youthful epigenetic pattern.

Effect 6: Healthy Aging

Researchers noted that protein restriction can extend not only the lifespan but also the healthy lifespan across several species. A British twin study found that higher-protein intake was associated with an increased risk for sarcopenia, whereas a low-protein Mediterranean diet was associated with greater muscle mass and strength.

One possible explanation for these partly conflicting findings is the source of the protein. Plant proteins, unlike animal proteins, have been associated with a lower risk for frailty.

Research led by Lamming found that although a high-protein diet can promote muscle growth, particularly with strength training, restricting dietary protein or specific amino acids can reduce age-related increases in frailty in animal models.

Physical activity can largely offset the loss of lean body mass associated with low-protein diets in humans. This could potentially allow individuals to benefit from protein restriction while maintaining muscle mass.

The long lifespan of the Okinawa population has been partly attributed to a protein-restricted diet containing about 9% protein. Okinawa is one of the “Blue Zones,” regions where individuals live to an above-average age.

However, about 80% of the calories consumed by the Okinawan population come from plant-based sources, and the overall calorie intake is also lower. Therefore, the benefits cannot be attributed solely to lower protein intake. Nevertheless, these observations support the possibility that protein restriction promotes healthy aging in humans.

Resilience With Age

Physical resilience, or the ability to withstand and recover from stressors, such as extreme temperatures, fasting, and infections, decreases with age. Cellular resilience, which refers to the ability of cells to respond to stressors, such as hypoxia, pathogens, and heat, also decreases. Loss of resilience contributes to chronic diseases, multimorbidity, and death and is influenced by diet, lifestyle, and genetic factors.

In Drosophila, protein restriction increases resilience during aging and improves responses to starvation, bacterial infections, and heat stress. However, its effects on resilience in mammals remain unclear.

Specific Amino Acids

Numerous studies have examined the effects of restricting individual amino acids, although most have been conducted using animal models. These studies suggest that restricting essential amino acids (EAAs) can reproduce some of the lifespan benefits of general protein restriction, whereas restricting nonessential amino acids (NEAAs) does not appear to extend lifespan. Methionine and the branched-chain amino acids such as leucine, isoleucine, and valine appear to have particularly important effects.

Methionine restriction extends the lifespan of many species. Isoleucine restriction consistently improved metabolic health in mice across different diet and age groups. Valine restriction reduces body weight, improves metabolic health, and extends the lifespan of male mice.

NEAAs can also influence specific aspects of aging. Glycine supplementation extended the lifespan of mice by 6.2% in males and 3.7% in females, whereas tyrosine restriction significantly extended the lifespan of Drosophila.

Overall, the researchers concluded that NEAAs may be as important to the aging process as EEAs and should be considered individually. Supplementation with some NEAAs could promote healthy aging, whereas reducing the intake of others could have beneficial effects on health and longevity.

Implications for Practice

The authors cautioned against the rapid translation of these findings into clinical practice. Determining the optimal protein and specific amino acid intake for individual health remains challenging.

Particular caution is required in vulnerable populations. Pregnant women, children, individuals following calorie-restricted diets, and those recovering from illness could be harmed by protein or amino acid restriction. Many older adults have inadequate protein intake because of factors such as reduced appetite, financial constraints, and social isolation. Therefore, further restricting protein or amino acids could increase their risk for deficiency.

Individuals who exercise regularly may have higher-protein requirements or, at a minimum, may be able to consume higher amounts of protein or specific amino acids without an increased metabolic risk.

Researchers view these findings primarily as a basis for further research on the relationship between dietary protein and aging. The goal is to translate these findings into concrete, personalized dietary recommendations.

https://www.medscape.com/viewarticle/protein-and-healthy-aging-could-less-be-more-2026a10010nm