Aging is a process that includes multiple interwoven mechanisms that interact with lifestyle factors. A new review seeks to encapsulate the available information on the effect of diet on aging at the cellular level in humans.

Review: The role of dietary strategies in the modulation of hallmarks of aging. Image Credit: UfaBizPhoto / Shutterstock

Introduction

Age is a universal factor that contributes to most chronic diseases. However, it is not inevitable at a specific age and may be considered malleable.

The hallmarks of aging occur at the systemic, cellular, and molecular levels. They include genomic instability, attrition of telomeres, epigenetic modification, reduced proteostasis, loss of nutrient sensing regulation, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and changes in intercellular communication. Furthermore, three new hallmarks have been identified: impaired macroautophagy, chronic inflammation, and dysbiosis associated with aging.

Dietary restriction (DR) and several dietary patterns have been studied for their ability to improve multiple health outcomes associated with aging, such as changes in body fat, insulin sensitivity, blood sugar levels, blood pressure, and inflammation.

The present question is whether it also can slow down the speed of aging in the cells. Earlier research shows that DR can stabilize the genome from undesirable changes that occur naturally but promote aging, preserves protein integrity, helps maintain the regulation of nutrient-sensing pathways that are important in energy homeostasis, and slow cellular aging processes. It also sustains beneficial intercellular communication.

Diets such as the Mediterranean diet (MD), the ketogenic diet (KD), and other plant-based diets have also been evaluated for their effectiveness in this field. Similar benefits have been reported. The researchers in the current study, published in the journal Ageing Research Reviews, sum up the potential for nutritional interventions to increase the healthy lifespan, exploring facets such as adherence levels, adverse effects, and broad-spectrum applicability.

What does the evidence show?

In general, DR shows reduced nuclear damage with a higher rate of DNA repair under calorie restriction (CR) conditions, at 30% to 55% of normal caloric intake, in rodents. Possible mechanisms include lowering the production of oxidants like hydrogen peroxide in the mitochondria or the leakage of free radicals in mitochondrial DNA (mtDNA).

Encouragingly, CR late in life still promotes the healing of oxidative damage and keeps the genome functioning by inducing DNA repair and increased debris removal by autophagy. This has not been found in non-rodent species, however.

CR did reduce DNA damage in humans in just six months while fasting between sunrise and sunset for two days a week (Muslims call this the Sunnah fast) produced similar results within six weeks, lasting for up to 36 months, despite CR being mostly below a fifth of normal.

As for epigenetic modifications that promote aging, preclinical but not human models indicate that 30% CR can reduce and reverse these changes. However, much more extensive studies are required in this area. In preclinical studies, DR has been observed to ensure proper disposal of toxic proteins, which is essential for proteostasis.

40% CR and intermittent fasting are associated with improved protein homeostasis, even with a high-fat diet. This could help prevent aging-related changes, especially in neurodegeneration.  

The MD model also promoted genomic health, as shown by improvements in various markers of DNA oxidation in humans. It also prevented telomere shortening, a sign of age-related disease in many conditions. Dietary energy restriction by 30% is also potentially beneficial in producing this effect, especially when fats, meats, and sweets are reduced.

Epigenetic modifications favorable to health were observed with MD-like diets but not with corn oil. MD could also activate autophagy to remove toxic proteins within the visceral white fat in obese adult women. This is perhaps due to the presence of polyphenols from olive oil and wine in this diet.

Protein restriction and a plant-based KD are potential interventions to increase autophagy and maintain proteostasis. Fasting, CR, and the MD seem to mediate better responses to nutrient sensing, extending the lifespan in preclinical studies, but further human studies are essential to establish the clinical utility of this response.

Replicative senescence is a circadian phenomenon in cells whereby the telomere progressively shortens during successive cell divisions, ending in growth arrest. However, senescence also follows cell damage through various mechanisms, whether mediated by oxidative or DNA damage or external stressors.  

The buildup of senescent cells can lead to deterioration in functional tissue, promoting faster aging and degenerative disease. However, 30% CR for a mean of ten years is reduced with reduced senescence in adults above 60. This may be reflected in reduced senescence-related markers when following the MD.

MD adherence is also associated with reduced inflammaging, a low-grade chronic inflammatory state that leads to tissue senescence, dysfunction, degeneration, and aging caused by altered cell communication. Interestingly, this is less obvious with DR.

What are the implications?

While CR is the nutritional intervention most often used in dietary experiments, it is not broadly applicable to humans, both because it is unappealing to most people and because it may cause psychological stress when followed over the long term. The selective restriction of some amino acids is still a research area.

Most research evidence points to the use of plant-based foods and the MD as helpful in slowing down aging-associated changes, but the KD appears, from the available studies, to be more specific in its effects.

Stem cell exhaustion is significantly related to tissue aging, hindering regeneration. Unfortunately, little evidence is available on the effects of CR or MD/KD on stem cell exhaustion, and this appears to be a wide-open field for future work.

Overall, “dietary restriction and certain dietary patterns, such as the Mediterranean dietary pattern, are nutritional strategies that can impact aging rates and the development of age-related clinical conditions.”

However, this cannot be applied with confidence or precision until more evidence is available from human studies using standardized methods in more significant numbers of people.

Journal reference:

• de Franca, N. A. et al. (2023). The role of dietary strategies in the modulation of hallmarks of aging. Ageing Research Reviews. DOI: https://doi.org/10.1016/j.arr.2023.101908. https://www.sciencedirect.com/science/article/pii/S1568163723000673