Alternative Dietary Strategies to Modulate Obesity and Improve Metabolic Health in Aging: A Comparative Narrative Review

Abstract

In aging, chronic diseases such as obesity accelerate metabolic dysfunction through chronic inflammation and insulin resistance. This review compared three different dietary strategies to evaluate their mechanisms and benefits for metabolic health and longevity. A comprehensive database search was conducted, selecting studies in animal models and in humans with or without obesity which have been published since 2004. Fasting-mimicking diets reduce IGF-1, promote autophagy, and improve insulin sensitivity, although long-term adherence remains a challenge. Time-restricted feeding synchronizes food intake with circadian rhythms, benefiting inflammation, glycemic control, and body composition. Protein and amino acid restriction, particularly methionine and branched-chain amino acids, modulates mTOR and reduces oxidative stress but requires adjustments in older adults. According to the available evidence, each intervention offers a non-invasive and adaptive approach to mitigating the effects of aging, provided it is applied in a personalized manner with appropriate follow-up.

1. Introduction

Dietary and nutritional interventions aimed at prolonging longevity and improving quality of life have proven to be key strategies in mitigating the effects of aging. Within this framework, obesity has emerged as a determining pathological factor that accelerates biological aging by inducing low-grade chronic inflammation, insulin resistance, and mitochondrial dysfunction, which contribute to the development of metabolic, cardiovascular, and neurodegenerative diseases [1]. In older adults, obesity may act as an accelerating factor of aging, particularly when it occurs alongside sarcopenia, which is characterized by a decline in muscle mass and strength, combined with an increase in fat mass—typically associated with a positive energy balance due to increased caloric intake and decreased energy expenditure. It is important to note that this condition strongly predisposes older individuals to frailty, thereby exacerbating their physiological deterioration.

In this context, dietary modulation presents itself as an accessible, safe strategy with significant potential to counteract these adverse effects and enhance metabolic resilience during aging.

Among the most extensively studied dietary strategies related to longevity, caloric restriction (CR) has been recognized as being one of the most consistent, with extensive evidence in animal models and some promising data in humans. However, its long-term clinical implementation has encountered challenges due to low adherence and the potential for side effects, such as reduced bone mineral density or decreased basal metabolic rate, which may compromise weight regulation in older individuals [2]. In response to these challenges, alternative strategies have emerged that aim to achieve the same benefits as CR without its limitations, leading to the evaluation of other dietary patterns with mimetic effects on metabolism and aging regulation.

Two of the most researched strategies are intermittent fasting (IF) and time-restricted feeding (TRF). Both have demonstrated favorable metabolic adaptations, including increased metabolic flexibility and reduced oxidative stress, with positive effects on inflammation and insulin sensitivity [3]. However, adherence to IF, particularly in protocols involving prolonged fasting periods, may be challenging for many individuals, prompting the search for more sustainable long-term strategies.

Within this context, new dietary approaches have been developed to optimize metabolic efficiency without compromising clinical applicability. This review analyzes three alternative dietary patterns with the potential to mitigate the effects of aging: fasting-mimicking diet (FMD), time-restricted feeding (TRF), and protein and amino acid restriction (PAAR). These strategies have gained increasing interest due to their ability to modulate key metabolic pathways, such as mTOR (mammalian target of rapamycin), IGF-1 (insulin-like growth factor 1), and AMPK (AMP-activated protein kinase), which play a central role in aging regulation and the accumulation of pathological adiposity.

FMD has been proposed as a viable alternative to induce the benefits of CR without requiring continuous caloric restriction. It has been shown to reduce IGF-1 signaling, increase autophagy, and improve insulin sensitivity, thereby lowering the metabolic risk associated with obesity [4]. In contrast, TRF is based on aligning food intake with circadian rhythms, which has demonstrated positive effects on glucose metabolism, systemic inflammation, and body composition in individuals with obesity and metabolic syndrome [5]. Finally, PAAR has been identified as a potentially effective strategy for longevity, as restricting specific amino acids, such as methionine and branched-chain amino acids, can modulate mTOR activation and reduce chronic inflammation. However, its applicability in older adults must be carefully considered due to its possible impact on sarcopenia [6].

Since obesity exacerbates the metabolic alterations associated with aging and represents a challenge in implementing sustainable dietary interventions, it is essential to assess the impact of these strategies on pathophysiological aspects such as insulin sensitivity, lipid profiles, blood pressure, and other indicators related to chronic degenerative diseases typical of aging, as well as their long-term clinical applicability. The objective of this narrative review is to provide a comparative analysis of the mechanisms and effectiveness of these three dietary strategies, emphasizing their potential to improve metabolic health, reduce obesity-related inflammation, and promote longevity

2. Materials and Methods

To develop this narrative review, an extensive bibliographic search was conducted in scientific databases to analyze and compare the impact of three alternative dietary strategies to caloric restriction (CR) in modulating aging and obesity. The search included MeSH terms and keywords such as caloric restriction, intermittent fasting, longevity, healthy aging, dietary modulation, obesity, and metabolism. Various combinations were adopted using Boolean operators to build combinations of these terms with the aim of maximizing the number of relevant articles retrieved from PubMed/Medline, Scopus, and Google Scholar.

The search period covered studies from 2004 to October 2024, as significant advancements have been made in the last two decades regarding dietary interventions related to aging and obesity [6]. Studies in animal models and humans were included, with particular attention paid to those evaluating the effects of time-restricted feeding (TRF), fasting-mimicking diets (FMDs), and protein and amino acid restriction (PAAR). Only articles written in English and Spanish were considered.

The initial search strategy identified 186 articles. After removing duplicates, 145 studies were screened by title and abstract. A total of 41 articles were selected for full-text review, and finally, 9 studies met the inclusion criteria:

• Experimental studies in animals or clinical/observational trials in humans.
• Well-defined dietary interventions: FMDs (fasting-mimicking diets), TRF (time-restricted feeding), or PAAR (protein and amino acid restriction).
• Quantifiable outcomes related to markers of healthy aging or metabolic health (body weight, IGF-1, insulin, lipids, inflammation, longevity).

Studies that were not directly related to the topic, those focusing on veterinary applications, or those that did not provide quantitative data were excluded. Conference abstracts, letters to the editor, and opinion pieces were also excluded.

It is worth noting that all studies ultimately included were published in English; no articles in Spanish met the inclusion criteria.

The selected studies were classified by the type of intervention and experimental model and were analyzed in detail in the Results and Discussion sections.

Special attention was given to including studies that provided detailed information on animal models, specifying whether the findings were derived from experiments in mice, rats, or other species more physiologically comparable to humans. Likewise, in human studies, variability in age groups, sex, and the metabolic conditions of participants were considered to offer a more precise analysis of the impact of these dietary strategies on obesity and aging.

To describe and explain the similarities and differences among the evaluated dietary patterns, a descriptive comparative approach was employed. Key elements of each strategy were identified, including the mechanisms of action and observed effects across different populations. Additionally, tables summarizing relevant findings from the selected studies were incorporated, allowing readers to clearly visualize the effects of each intervention in both animal models and humans (Figure 1).

3. Results and Discussion

A total of nine studies were selected after applying the inclusion criteria defined in the Methods section. Of these, five were conducted in animal models and four in humans, covering the three dietary strategies of interest: fasting-mimicking diets (FMDs), time-restricted feeding (TRF), and protein and amino acid restriction (PAAR). The distribution was balanced, with three studies per strategy.

The human studies included both younger and older adults, most of whom had conditions such as overweight, obesity, metabolic syndrome, or frailty. In animal models, the research focused on mice—particularly the C57BL/6 strain—using protocols designed to simulate clinical contexts such as diet-induced obesity or physiological aging.

Regarding FMDs, human studies reported improvements in parameters such as fasting glucose, blood pressure, and hormonal markers (IGF-1 and leptin), without compromising lean body mass. In animals, intermittent FMD cycles were associated with positive effects on key organs such as the pancreas and brain, showing significant functional and metabolic improvements. Reductions in visceral fat and a moderate increase in lifespan were also observed.

In the case of TRF, the human protocols showed positive effects on body mass index, blood pressure, plasma lipids, and functional mobility—even in the absence of explicit caloric restriction. In murine models, this pattern supported improved insulin sensitivity, weight control, and lipid modulation, suggesting broad benefits even without energy reduction.

Lastly, studies on PAAR showed that limiting the intake of certain amino acids—such as methionine and BCAAs—in animals improved markers of inflammation, insulin sensitivity, and longevity. In humans, observational studies indicated that a low-protein diet, particularly low in animal protein, was associated with reduced cancer mortality and improved lipid and glycemic profiles in middle-aged adults.

Detailed information from the selected studies, including type of intervention, model, duration, evaluated variables, and main findings, is presented in

Table 1. Characteristics of included studies by dietary strategy.

Author	Dietary Strategy	Model	Population/Species	Study Duration	Variables Measured	Key Findings
Matson et al. (2017) [3]	TRF	Human	Adults with obesity	12 weeks	Weight, HOMA-IR, blood pressure	Weight: −4–6%; HOMA-IR: −25%; systolic BP: −7 mmHg
Brandhorst et al. (2015) [7]	FMD	Human	Overweight adults	3 cycles/3 months	Glucose, IGF-1, leptin	IGF-1: −15%; leptin: −20%; fasting glucose: −11 mg/dL; no lean mass loss
Fontana et al. (2015) [8]	PAAR	Animal	C57BL/6 mice	6 months	Longevity, visceral fat	Lifespan: +30%; visceral fat: −20%
Longo et al. (2014) [9]	FMD	Animal	Mice	4-day cycles every 2 weeks	Autophagy, pancreatic regeneration	Enhanced beta-cell regeneration; increased autophagy
Madeo et al. (2019) [10]	PAAR	Animal	Mice (low methionine)	6 months	Inflammation markers (IL-6, TNF-α), IGF-1	IL-6 and TNF-α: −30%; IGF-1: −25%
Mattson el al. (2018) [11]	FMD	Animal	Mice	Intermittent	Cognitive function	Dopaminergic neuron loss: −30%; neuroprotection in Parkinson model
Panda S. (2016) [12]	TRF	Animal	Obese mice	12 weeks	Weight, LDL cholesterol	Weight: −10%; LDL: −20%
Levine et al. (2014) [13]	TRF	Human	Older adults with frailty	4 weeks	BMI, gait speed	BMI: -5%; gait speed: +5%
Solon-Biet et al. (2015) [14]	PAAR	Human	Adults aged 50–65 (observational)	Cross-sectional	Cancer mortality, IGF-1	Cancer mortality: −75%; IGF-1: −20%; lower LDL and triglycerides

TRF: Time-Restricted Feeding. FMD: Fasting-Mimicking Diet. PAAR: Protein and Amino Acid Restriction. HOMA-IR: Homeostasis Model Assessment of Insulin Resistance. BP: Blood Pressure. IGF-1: Insulin-like Growth Factor 1. IL-6: Interleukin 6. TNF-α: Tumor Necrosis Factor Alpha. LDL: Low-Density Lipoprotein. BMI: Body Mass Index.

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4. Discussion

Aging as a biological process is subject to the intervention of certain metabolic processes that help to explain its development, as well as the presence of specific conditions associated with aging that are chronic and degenerative, deteriorating an individual’s quality of life and accelerating the aging process. Obesity, considered a significant metabolic imbalance, exacerbates these processes by promoting chronic inflammation and insulin resistance, increasing the risk of aging-associated complications.

The objective of dietary and nutritional modulation is based on influencing the different metabolic pathways involved in aging to limit, as much as possible, the increasing organic dysfunction it causes. Studies conducted in animal models indicate that diet can intervene in different signaling pathways implicated in the senescent process.

It is necessary to have a broad understanding of the affected signaling pathways that may be modulated by the different dietary interventions aimed at promoting longevity in the experimental models. The resulting physiological adaptations are linked to health benefits that are considered translatable to humans and would form the fundamental basis of interventions capable of mitigating the pathological processes associated with aging [15].

In general, the dietary strategies employed are based on limiting energy intake and/or modifying the proportions of nutrients provided by the diet.

Thus, it is observed that limiting carbohydrate intake, which is the main energy nutrient, results in lower glucose availability and dihydroxyacetone phosphate levels, which, when detected by AMP-activated protein kinase (AMPK), lead to an increase in its activity, activating TSC (tuberous sclerosis complex), which reduces mTORC1 activity through the Rag-GATOR pathway. This effect reduces ribosomal biogenesis, protein synthesis, and increases autophagy. In animal models, these adaptations led to a significant reduction in visceral and subcutaneous adipose tissue, decreasing total fat mass by approximately 15–20% [16].

Lower energy and carbohydrate intake results in reduced insulin/IGF-1 signaling, leading to lower phosphoinositide 3-kinase (PI3K) activity, which in turn reduces mTORC2 activity and increases FOXO (Forkhead Box O1), a transcription factor involved in energy regulation, cell cycle processes, and protecting against oxidative stress, and, in animal models, has been shown to reduce the expression of IL-6 and TNF-α, improve adaptive immunity parameters, and decrease the incidence of aging-associated tumors [16]. Likewise, in rats with induced obesity, modulation of the insulin/IGF-1 pathway showed improvements in insulin sensitivity and reduced inflammatory markers, suggesting a fundamental role of this pathway in metabolic aging.

Reducing dietary protein intake, specifically branched-chain amino acids (BCAAs) and methionine, activates the Rag-GATOR pathway, producing the same effects as energy restriction, such as mTORC1 inhibition. Additionally, GCN2 (general control nonderepressible 2) activation leads to increased F2α and ATF4 (activating transcription factor 4), which induce increased FGF21 (fibroblast growth factor 21) activity, related to greater longevity (+30% in murine models) and a significant reduction in adiposity, insulin resistance, and systemic inflammation [16].

In the case of methionine restriction, it results in lower S-adenosylmethionine (SAM) availability, an element involved in the methylation processes of both DNA and histones, leading to molecular alterations and damage. These negative effects are minimized by reducing the intake of this amino acid.

It is important to highlight that sirtuin activity also increases, which, in collaboration with other pathways, activates critical cellular stabilization processes such as autophagy and mitophagy. These mechanisms stimulate genetic material repair systems and antioxidant defenses and lead to greater efficiency in stem cell renewal.

The result of all these actions implies improved proteostasis and reduced cellular senescence, facilitating greater cellular and organic functionality, which are observed in animal models as an increase in regenerative capacity and an improvement in the functionality of organs such as the liver, skeletal muscle, and brain.

In summary, dietary modulation influences various cellular functions [16], such as the following:

• Increased proteostasis;
• Enhanced autophagy and mitophagy;
• Greater efficiency in repairing DNA damage;
• Reduced oxidative stress;
• Decreased senescent cell population;
• Increased stem cell renewal capacity.

These actions provide protective effects against chronic conditions associated with aging, including autoimmune diseases, neurodegenerative disorders, and kidney diseases. In animal models, these adaptations have been shown to reduce the incidence and severity of aging-related metabolic disorders by 20–40%, lowering markers such as IL-6 and TNF-α by 15–30%, thereby improving systemic inflammation, enhancing insulin sensitivity (20–25%), and delaying the onset of cognitive deficits [16], allowing for significant improvements in the quality of life of elderly individuals, ultimately slowing the aging process and increasing longevity.

Broadly speaking, dietary modulation enables epigenetic, transcriptional, proteomic, metabolomic, and microbiome-related modifications that promote the benefits indicated in Figure 2.

• Evaluated Dietary Patterns

4.1. Fasting-Mimicking Diets (FMDs)

This dietary regimen has the potential to produce effects like caloric restriction (CR) [17], as it allows for a controlled intake of nutrients while maintaining the benefits of fasting dietary patterns, facilitating long-term adherence.

It is a structured dietary formula composed of specific foods and a defined energy restriction that combines the characteristics of CR and intermittent fasting (IF) to enhance long-term compliance. Its practical implementation usually lasts between three to five consecutive days, providing a degree of flexibility in execution and allowing for sustained adherence. It has also been suggested that it can consist of a very low-energy vegetarian diet consumed for four consecutive days in two periods per month [18].

The implementation of an FMD protocol applied cyclically in overweight middle-aged adults (2 cycles per month for 3 months), providing 55% of their daily energy needs on the first day followed by 35% on the subsequent four days, resulted in a reduction in fasting glucose (~11 mg/dL), a decrease in IGF-1 levels (15–20%), and a drop in systolic blood pressure (4–7 mmHg), without the loss of lean mass (11). In animal models, the intervention was typically limited to 4 days of FMD every two weeks, showing an increase in lifespan (~11%) and a reduction in tumors (~45%) [7]. Studies have indicated that individuals experience reductions in blood glucose and IGF-1 levels, while circulating ketone bodies increase. In humans undergoing FMD, a reduction in visceral fat mass of approximately 3–6% was observed after three intervention cycles (11).

This dietary approach is highly versatile and has been used as an adjunct treatment for hormone receptor-positive breast cancer, combined with hormone therapy. Metabolic changes such as reduced leptin, IGF-1, and insulin levels have been observed. The first two markers remain low for extended periods, an effect associated with long-term anticancer activity in experimental animal models, with a sustained reduction in leptin and IGF-1 being associated with decreased tumor progression. Preliminary human trials combining FMD with hormonal therapy in breast cancer have shown a decrease in serum levels of leptin, IGF-1, and insulin [18].

Similar effects have been observed in animal models, where, it has been shown to partially restore pancreatic β-cell function in type 2 diabetes (12), improve gut microbiota composition and reduce intestinal inflammatory markers (13), as well as preserve dopaminergic neurons in murine models of Parkinson’s disease, reducing neuronal loss by approximately 30% [19,20,21].

Moreover, studies in humans show that through applying this dietary pattern, a significant improvement in cognitive test scores has been observed (an increase of 2–3 points on the MMSE test), along with a decrease in biomarkers related to the progression of Alzheimer’s disease, including a 15–20% reduction in plasma β-amyloid levels [22]. Some of these effects may be relevant for anti-aging interventions, as they are linked to age-related pathologies.

Although the results of this dietary practice are promising, adherence does not appear to be its strong point. However, since the protocol is limited to around ten days per month, it may, in many cases, be better accepted than other more restrictive approaches.

4.2. Time-Restricted Feeding (TRF)

Another dietary approach evaluated in this review is time-restricted feeding (TRF), which involves eating within a limited time window of less than 10 h per day without reducing total caloric intake.

This dietary protocol is based in animal studies, where it has been shown to prevent obesity, improve insulin sensitivity, and reduce the accumulation of hepatic and plasma lipids [23]. In humans, reducing the eating window to 8–10 h has improved metabolic parameters such as blood pressure, circulating lipids, and glycemic control [24,25].

In this case, energy restriction is not the focus. Instead, circadian rhythm regulation is emphasized, as synchronizing food intake with biological rhythms elicits a beneficial metabolic response. Restricting food intake to the active phase (daytime in humans) may prevent metabolic disturbances and weight gain.

Several studies have investigated the short-term impact of TRF in adults with obesity, aiming to reduce the metabolic damage associated with excess fat mass.

One study implemented a protocol in which participants consumed food within an 8 h window each day for three months. The results showed a notable reduction in blood pressure as well as body weight, and a mild caloric restriction [24]. In this case, an intervention was implemented by limiting the daily feeding window to between 6 and 10 h over periods ranging from 4 to 12 weeks, without caloric restriction, but with an adjustment of the start time of the window to the active (daytime) phase [24]. In adults with obesity or metabolic syndrome, this program resulted in a body weight reduction of approximately 3–8%, a decrease in systolic blood pressure of up to 7 mmHg, and a reduction in fasting insulin and HOMA-IR of 20–30% [24,25,26]. In animal models, TRF is typically applied with feeding windows of 8–12 h and has been shown to prevent obesity and improve insulin sensitivity even in the absence of caloric restriction [23].

Another study included adults diagnosed with metabolic syndrome, where food intake was restricted to a 10 h window without reducing calorie intake or altering macronutrient proportions. Physical activity levels remained unchanged, yet the participants showed reductions in triglycerides and LDL cholesterol of approximately 10% and systolic blood pressure of 5 mmHg [25].

A study with a greater focus on anti-aging treatments evaluated overweight or obese adults aged 65 and older with mobility impairments or with a high risk of developing them. The participants followed an 8 h eating window for one month, resulting in significant weight loss which was manifested by a 5–7% reduction in BMI (body mass index) and a 5% improvement in walking speed and functional capacity (as measured by the timed walk test), indicating enhanced mobility and a lower risk of frailty. This finding is particularly relevant, considering that frailty is a major dysfunction accelerating physical deterioration in aging [26].

It is possible that the length of the eating window influences results. In protocols restricting food intake to 6 h per day where the last meal was consumed before 3:00 PM, pre-diabetic men following this approach for five weeks exhibited significant improvements in β-cell function, insulin sensitivity, as well as an approximate 3% reduction in body weight over five weeks [27].

Although some studies argue that reducing the feeding window does not always yield superior results, additional data are needed to draw definitive conclusions. More clinical trials with significant statistical power are required to assess how factors such as age and sex influence the efficacy of these interventions. Animal models strongly indicate that time-restricted feeding has considerable potential, but human studies remain limited [28].

Although the results obtained with TRF are promising, they must be interpreted with the consideration of important individual differences. Factors such as age, sex, body composition, and personal chronobiology (chronotype) can modulate the metabolic response to TRF, as synchronizing feeding windows with circadian rhythms is essential to obtain the desired benefits [29,30].

Moreover, it is important to clarify that the effects of TRF described in controlled studies are not directly translatable to other forms of prolonged fasting, such as those observed in religious contexts (e.g., Ramadan), where meals are concentrated during the night or early morning, often resulting in significant circadian misalignment [28]. The available evidence suggests that misalignment between the feeding window and endogenous rhythms could limit or even reverse some of the metabolic benefits observed with TRF [29].

Therefore, when considering the implementation of these dietary strategies, both individual characteristics and the cultural and social factors that shape eating patterns must be considered.

A key distinction between this approach and caloric restriction-based interventions is that TRF does not involve a reduction in energy intake. This suggests that the observed effects may stem from mechanisms beyond caloric deficit, possibly linked to circadian regulation rather than simple energy reduction.

This dietary approach appears to stimulate the activity of circadian genes related to autophagy, as well as the expression of circadian-regulated genes, which are dependent on the fasting window. Functional circadian clocks are required for these effects to occur [29,30], especially when the time-limited feeding pattern is combined with intermittent intake. It has been demonstrated that the presence of a fully functional circadian clock is essential for time-restricted feeding to provide anti-aging benefits [29].

In this regard, the mechanisms underlying TRF’s anti-aging effects differ from those of caloric restriction. It has been hypothesized that autophagy, a cellular process activated under stressful conditions such as fasting, plays a crucial role. Autophagy activation follows a rhythmic pattern aligned with the circadian cycle, reinforcing the idea that TRF could enhance autophagy gene expression, thereby facilitating its beneficial effects.

One study [30] demonstrated that the critical genes for effective autophagy follow a circadian regulation pattern, reaching their peak during nocturnal fasting periods. This suggests that TRF could increase the expression of autophagy genes, contributing to anti-aging benefits.

The study provided sufficient evidence to support the derivation of time-restricted eating (TRE) as a useful adjunctive dietary strategy for combating aging. However, our understanding of circadian-regulated autophagy is still incomplete. Although its role appears essential in the effectiveness of TRE [30], the most appropriate ways to stimulate this mechanism remain unclear. Therefore, further research is needed to deepen our knowledge of this pathway and its potential in anti-aging interventions. A major advantage of TRF compared to other dietary interventions is that adherence appears to be relatively high if individuals maintain a consistent fasting period and avoid overconsumption during eating windows. This suggests that TRF could be integrated as a clinically relevant intervention, especially when considering its potential to reduce cardiometabolic risk factors.

4.3. Dietary Protein and Amino Acid Restriction

Dietary manipulation can be a valuable intervention for delaying, preventing, or treating many aging-related diseases. In fact, these effects could be actively used to slow down the progression of aging.

One of the most studied dietary modifications in terms of nutritional modulation consists of dietary restriction of the consumption of certain amino acids and the restriction of the total amount of protein.

Findings from different studies in animal models suggest a significant decrease in comorbidities related to the aging process, a decrease in the incidence of metabolic and neoplastic diseases, and an up to 30% extension in lifespan [31,32], although their translation to human life may not be as simple or probably as satisfactory.

In most of the reviewed studies, the applied protein restriction ranged from approximately 0.8–1.2 g/kg/day for moderate restriction to <0.8–1.0 g/kg/day for more stringent protocols [31,33], which are lower than the usual intake observed in Western diets (1–1.4 g/kg/day). Additionally, some trials indicated that the specific restriction of certain amino acids—particularly branched-chain amino acids (BCAAs) and methionine, which actively regulate mTORC1, autophagy, and longevity-related pathways—also contributed positively. These interventions have shown improved insulin sensitivity, reduced IGF-1 levels, and an extension in lifespan of up to 30–50% in experimental animal models, depending on the degree of restriction [32,33,34].

Accordingly, BCAA restriction has demonstrated effects in animal models that are very similar to those observed with caloric restriction.

Reducing the proportion of proteins in the diet, especially in older individuals, may pose some challenges despite its benefits against age-related diseases, as it could compromise immune system efficiency, wound healing, and predispose individuals to sarcopenia, particularly in those with limited physical activity. This represents a major controversy, and these interventions may need to be assessed on a highly individualized basis before being implemented as a dietary treatment for aging.

The literature has extensively illustrated the results of numerous research studies in animal models that have associated limited protein intake with a reduction in aging-related health problems and even an increase in longevity; thus, protein and methionine or BCAA restriction reduces visceral adiposity, improves insulin sensitivity, lowers systemic inflammation, and extends the lifespan by 30–50%, depending on the species and protocol used [31,32,33].

The underlying mechanisms are related to changes in signaling pathways due to the reduction in protein intake, specifically involving IGF, growth hormone, and mTOR.

When evaluating the effectiveness of this dietary proposal, the question arises of whether the limited protein intake itself is responsible for these effects or if they are instead due to a possible caloric restriction that would naturally lead to a lower protein intake.

Studies in experimental animals have shown that the effect of caloric restriction is greater than that of protein restriction, although the benefits of protein restriction should not be dismissed [31].

To analyze the value of dietary protein restriction in longevity and especially in limiting the presence of aging-related diseases, it is essential to consider the source (animal or plant-based), the quantity, and the type of amino acids that make up the proteins, particularly considering the influence of restricting branched-chain amino acids and methionine.

Likewise, studies that incorporate nutritional geometry approaches have shown that the proportion of macronutrient content in the diet can have a very significant influence on the development of aging, including health-related conditions specifically. A diet low in protein and high in carbohydrates has been shown in animal models to extend lifespan (+30%) and improve glucose tolerance, blood pressure, and the lipid profile. [32].

The molecular and physiological mechanisms that lead to improved metabolic health when the intake of certain amino acids is reduced [33] do not differ from those induced by caloric restriction. Thus, it has been observed that the following protein-restricted diets affect the following signaling pathways:

• The mTORC1 complex and autophagy;
• The metabolism of S-adenosylmethionine (SAM) and glycine N-methyltransferase (Gnmt);
• Fibroblast growth factor 21 (FGF21);
• Growth hormone/insulin-like growth factor-1 (GH/IGF-1) signaling;
• Hydrogen sulfide;
• Oxidative stress and inflammation.

Studies conducted in animal models using tools such as nutritional geometry have indicated that the proportions of macronutrients in the diet play a significant role in metabolic health, which in turn impacts the aging process.

Nutritional geometry is an ideal dietary modeling method for understanding the most suitable nutrient compositions to define a nutritional balance between macronutrients and energy intake that yields the best outcomes in slowing down the negative progression of aging.

Findings from research in animal models have provided evidence of a significant positive effect on longevity when diets contain a high proportion of carbohydrates relative to proteins, while the opposite occurs when carbohydrate-to-protein ratios are inverted [34].

In these studies [33,35], it has also been observed that the best results, both in terms of increased life expectancy and health markers such as improved glucose tolerance, lower blood pressure, and significant reductions in circulating lipids and adiposity, are achieved with high-carbohydrate, low-protein diets, where caloric restriction has a more limited influence.

At the human level, findings from studies [13] have shown that a reduced protein intake (<10% of total energy) was associated with a lower all-cause and cancer-specific mortality, as well as improved glucose tolerance, which was correlated with findings from animal models regarding the benefits that this type of dietary approach provides against factors limiting metabolic health. The best outcomes were observed when dietary protein intake was below 10% of the total energy contribution in adults aged between 50 and 65 years, where a reduction in cancer-related mortality of more than 75% was observed, along with an improved lipid profile due to a 10–15% reduction in LDL cholesterol and triglycerides and a decrease of approximately 10 mg/dL in fasting blood glucose [13].

This study revealed that overall mortality and cancer-related mortality were significantly higher in individuals aged 50 to 65 years whose diet was very rich in protein; conversely, a low-protein intake reduced the risk of cancer-related death more than fourfold.

Interestingly, in older individuals (>66 years), the findings regarding diet type and mortality were reversed, showing better health indicators with high-protein dietary approaches. Additionally, IGF-1 blood levels did not change in older adults, whereas in younger individuals who consumed a low-protein diet, IGF-1 levels did decrease.

The conclusions suggest that, in middle-aged individuals, mortality, particularly cancer-related mortality, is significantly reduced, whereas in older individuals, protein intake should be increased, since it does not negatively impact mortality. Moreover, this increase would be notably beneficial in preventing sarcopenia and frailty, two highly detrimental factors in older individuals that contribute significantly to increased mortality.

Another important aspect to consider is the source of the consumed proteins, as it could have a critical influence on their effectiveness in preventing severe health problems, beyond their total amount.

According to long-term studies on protein origin and mortality risk [36], the regular consumption of plant-based proteins consistently reduces the risk of all-cause mortality, whereas animal-derived proteins, particularly red meat and processed meat products, show the opposite effect, with a significant increase in CVD incidence.

This suggests that the plant-based origin of dietary protein may act as a long-term protective factor for health.

Additionally, these studies have evaluated whether switching to plant-based protein sources could reduce mortality (20–30%) outcomes related to metabolic diseases such as obesity, CVD, and cancer in middle-aged individuals [36], leading to the conclusion that the source of dietary protein is a crucial factor in determining long-term health outcomes.

For individuals aged 50 to 65 years, the most recommended dietary approach for achieving a protective effect against degenerative diseases is consuming a diet that contains a limited amount of protein, with many of these proteins being derived from plant-based sources.

When discussing healthy dietary patterns, the elimination of any food group from the diet should not be considered. Although it has been demonstrated that animal-based proteins, particularly red meat and processed meats, have been associated with an increased risk of degenerative diseases [37], the benefits that these types of foods provide to humans should also be considered, as red meats are a good source of vitamins, zinc, and especially iron, as well as some essential amino acids necessary for proper physiological function.

This suggests that the determination of a dietary treatment should be personalized, following a detailed nutritional evaluation of the individual.

Not only is total protein intake related to the development of aging and its associated conditions, but also, the levels of specific amino acids present in the diet appear to have an even stronger correlation than the amount and/or type of proteins consumed.

Branched-chain amino acids (BCAAs) are nutrients whose excessive levels may negatively impact metabolic health and aging. The application of low-protein dietary patterns (<10% of total dietary energy) is beneficial both for metabolic health and for slowing aging, as indicated in previous studies.

A further step in this strategy is derived from a study [38] conducted in experimental animals, where the effects of following a diet low in branched-chain amino acids were evaluated, yielding similar benefits to those induced by caloric restriction (CR) in metabolic health. This leads to the hypothesis that other mechanisms related to these specific nutrients may be involved, apart from the quantitative reduction in total protein intake, making protein quality an essential determinant in metabolic health and aging outcomes.

Epidemiological data from studies have indicated that higher circulating concentrations of branched-chain amino acids correlate with insulin resistance, particularly in individuals with obesity and cardiovascular diseases [39,40].

On the other hand, it is impossible to ignore that the dietary inclusion of branched-chain amino acids (BCAAs) offers nutritional advantages, as they are associated with greater energy efficiency by supporting mitochondrial function and reducing oxidative stress in muscle fibers. This has long been utilized by athletes, and in recent years, new expectations have emerged in anti-aging medicine, as BCAAs may serve as a tool to counteract sarcopenia, which is common in older adults.

This presents a contradictory situation, as high BCAA intake has been linked to negative metabolic effects in obese individuals, particularly insulin resistance, while excessively low BCAA consumption may be harmful in older adults, particularly those with physical frailty and sarcopenia.

Once again, it is necessary to consider personalized dietary interventions, adapting intake based on individual needs to optimize therapeutic outcomes.

One amino acid extensively studied for its relationship with aging is methionine. There is evidence of its involvement in longevity-related processes, and it appears to play a direct role in the progression of senescence through various mechanisms.

Methionine restriction has been shown to increase metabolic flexibility, leading to enhanced lipid metabolism, improved insulin sensitivity, and reduced systemic inflammation [41].

Some studies have demonstrated that low-methionine diets improve metabolic health by reducing adiposity, as they increase basal energy expenditure and prevent fat accumulation.

Furthermore, as previously mentioned, insulin sensitivity is a key determinant of metabolic health. In this regard, it has been observed that methionine-restricted diets at 2 mg/kg/day enhance insulin sensitivity and significantly increase lipid oxidation [42], leading to a consistent reduction in hepatic fat content in individuals with metabolic syndrome.

In summary, food sources, intake levels, amino acid composition, and particularly the quantity of branched-chain amino acids and methionine are directly related to metabolic health and aging-related conditions, thus having a crucial impact on the aging process.

From a dietary selection perspective, it is possible to adopt a nutritional approach where total protein intake is reduced, but as previously mentioned, excessive protein restriction at certain ages may not be advisable, and alternative strategies might be more suitable to slow down the aging process.

In this regard, methionine reduction may be a viable alternative to severe protein restriction. Mediterranean-style diets could be considered effective dietary interventions for aging and its associated pathologies, particularly when plant-based proteins are emphasized, as animal-derived foods tend to have significantly higher methionine levels.

• Comparison of the Three Dietary Patterns

A comparative analysis has been conducted to evaluate different aspects of the three dietary strategies, assessing their mechanisms of action and their potential clinical impact on slowing the aging process and mitigating aging-related diseases.

At the molecular level, the effects of these interventions on autophagy, inflammation, insulin sensitivity, sirtuin activation, key signaling pathways, and cellular renewal have been analyzed, as these factors are closely involved in aging progression.

A comparative table (

Table 2. Comparison of dietary strategies to promote longevity and metabolic health (animals and humans).

Aspect	Fasting-Mimicking Diets (FMDs)	Time-Restricted Feeding (TRF)	Dietary Protein and Amino Acid Restriction (PAAR)
Description	Diets that mimic the effects of prolonged fasting but allow for controlled intake during specific periods [8,9].	Restriction of food intake to a reduced feeding window (typically 6–10 h per day) without caloric reduction [3].	Reduction in total protein intake or specific amino acids, such as methionine and branched-chain amino acids (BCAAs) [10].
Benefits
In humans	Reduced glucose, increased ketones, potential cancer prevention [3,7].	Reduced lipids and BP; weight loss; improved insulin sensitivity [12,13].	Lower cancer incidence and metabolic improvement in low-protein diets [7,14].
In animals	Increased ketosis and autophagy; improved mitochondrial function; reduction in IGF-1 [9,10,11].	Improved insulin sensitivity and autophagy [3].	Reduced adiposity, improved insulin sensitivity, reduced inflammation [7,8].
Limitations
In humans	Adherence issues, preliminary longevity data [3,10,11,14].	More trials are needed; adherence varies with time-window length. Requires circadian alignment for benefits [12,13].	Protein reduction must be personalized, especially in older adults. Sarcopenia risks are present with excessive restriction [7,14].
In animals	Demonstrated benefits, but not always translatable [9].
Examples of Studies
In humans	Showing benefits in breast cancer patients [7].	Improved mobility and weight reduction in older adults [13].	Longevity and reduced disease with low-protein diets [10,14].
In animals	Reduced metabolic and neurodegenerative diseases [8,9].	Prevented obesity and improved glucose tolerance [23].	Reduced cancer risk with protein restriction in middle age [7].

) has been created to facilitate the reader’s understanding, presenting the observed benefits, the limitations of the three evaluated dietary strategies, and examples of studies conducted in animal models and humans.

Regarding the clinical impact and practical feasibility of these dietary strategies, their effects on longevity, chronic disease prevention, and adherence to dietary treatments have been compared.

In the case of fasting-mimicking diets (FMDs), studies in animal models have shown an increase in longevity with this type of diet, although evidence in humans remains preliminary [8,9].

However, FMD significantly reduces the risk of metabolic diseases, neurodegenerative conditions, and certain types of cancer, such as breast cancer [7].

Long-term adherence is challenging, as FMD requires periods of low energy intake, which can be difficult to maintain [9,10]. Despite its benefits, the difficulty in maintaining this dietary pattern limits its widespread clinical application [7].

Regarding time-restricted feeding (TRF), long-term clinical trials remain limited, but current evidence suggests that it has metabolic health benefits, which could potentially influence longevity [11,14].

TRF has been found to be effective in reducing the risk of cardiometabolic diseases, such as type 2 diabetes and hypertension, due to its ability to improve insulin sensitivity and decrease inflammation [12].

In this case, adherence is considered easier, as TRF does not require strict caloric restriction, only adjusting feeding schedules, which enhances its viability across different populations [11,14]. Although human studies remain limited, its simplicity and alignment with circadian rhythms make it a suitable strategy for most individuals [12].

Protein and amino acid-restricted diets have demonstrated that reducing protein intake, particularly from animal sources, may extend lifespan. In humans, these effects are most evident in middle-aged individuals [10,13].

This dietary approach can reduce the risk of metabolic diseases, cardiovascular conditions, and cancer, particularly when the consumed protein is of animal origin. However, recommendations should be individualized, as in older adults, increasing protein intake can help prevent sarcopenia and frailty [7].

In terms of adherence, this diet is relatively easy to follow, but populations accustomed to high-protein diets (such as Western diets) may find its implementation more challenging. Therefore, personalization is necessary to avoid adverse effects in older adults [10,13].

This dietary pattern appears to be highly viable for middle-aged individuals at high risk of metabolic diseases or cancer, while in older adults, protein intake should be increased to prevent sarcopenia [7].

Table 3. Comparative summary of dietary patterns on longevity, chronic disease prevention, and adherence (animals and humans).

Aspect	Fasting-Mimicking Diets (FMDs)	Time-Restricted Feeding (TRF)	Dietary Protein and Amino Acid Restriction (PAAR)
Effect on Longevity
In humans	Evidence is still preliminary [8,9].	Some benefits shown in middle-aged individuals [11,13].	More modest evidence, especially in middle-aged adults [10].
In animals	Increases longevity [8,9].	Improves metabolic health markers associated with longevity [8].	Extends lifespan by up to 30–50% depending on protocol [10,14].
Chronic Disease Prevention
In humans	Decreases IGF-1 and glucose, improves risk markers [7].	Reduces BP and lipids, improves HOMA-IR [24,25].	Lowers LDL, triglycerides, and cancer risk in middle-aged adults [7,14].
In animals	Reduces incidence of neurodegenerative and metabolic diseases [7].	Prevents obesity, improves insulin sensitivity [12].	Reduces visceral adiposity and systemic inflammation [10].

presents a comparative summary of dietary patterns on longevity, chronic disease prevention, and adherence.

In essence, the comparative analysis determines that the three studied dietary patterns offer significant potential for improving health during aging. By activating key metabolic pathways such as mTOR and sirtuins and reducing pro-inflammatory factors like IGF-1, these strategies may promote longevity and prevent common chronic diseases in old age [7,8,9]. mTOR inhibition and autophagy activation are particularly relevant to cellular health and the prevention of neurodegenerative and metabolic diseases, as they facilitate the removal of damaged proteins and enhance cellular renewal, contributing to longevity [3,10].

Although evidence from animal models supports the potential benefits of these dietary approaches, human studies also show promising results. Specifically, protein intake reduction in middle-aged individuals has been associated with a lower risk of cancer and cardiovascular diseases [13]. Similarly, TRF has been shown to improve cardiometabolic markers and health outcomes in adults with obesity and metabolic syndrome, suggesting potential clinical benefits [11,14]. These patterns, applied in human populations in a controlled manner, are capable of reducing cardiometabolic risk factors such as glucose, circulating lipids, and blood pressure by 10 to 30%, in addition to improving cognitive function in individuals with mild impairment and reducing adiposity, offering a non-invasive and effective strategy capable of improving quality of life in aging [13,24,25,36]. At the clinical level, these dietary interventions could be integrated into gerotherapeutic strategies to promote health and functionality in aging, potentially complementing or even replacing certain pharmacological interventions, which often carry adverse side effects [3,7]. For example, fasting-mimicking diets (FMDs) could be used intermittently in patients at high risk of metabolic diseases, while protein and amino acid restriction (PAAR) could be personalized for individuals with genetic predisposition or a family history of cancer [10,13]. Time-restricted feeding (TRF), due to its ease of adherence over the long term, could be applied in a broader clinical setting, helping older adults and those with mobility limitations to improve cardiometabolic health without requiring strict caloric restriction [11,12]. However, it should be noted that some factors associated with aging (e.g., sarcopenia, chronic inflammation, comorbidities) can negatively influence the effectiveness and results of dietary strategies proposed in older adults, making it even more necessary to appropriately select the dietary intervention, individualizing it as much as possible.

Personalizing these dietary strategies and combining them with other nutritional interventions, such as the Mediterranean diet or the DASH diet, could offer tailored and effective approaches for preventing aging-related diseases. However, further research is needed to evaluate how these dietary patterns affect different age groups and to determine their effectiveness in combination with other dietary and lifestyle interventions [14].

4.4. Study Limitations

Most current studies on these dietary patterns have been conducted in animal models or short- and medium-term human studies, limiting the full understanding of their long-term effects on longevity and human health. Although some human research has shown positive effects on risk factor reduction and metabolic health improvement, significant increases in longevity have yet to be observed, given the limited duration of the studies [3,11]. To confirm the long-term benefits, it is essential to conduct longer and more controlled clinical trials that assess lifespan and quality-of-life impacts in individuals of different ages and with different health conditions [7,13].

Another important limitation is the lack of studies analyzing differences in effects based on sex and age. Metabolic needs and chronic disease risks vary considerably between men and women, and these differences could influence the effectiveness of these dietary patterns on health and longevity [12]. Moreover, age is a critical factor in the effectiveness of dietary interventions, as metabolic responses change with aging, meaning that what is effective for a middle-aged person may not be suitable for an older adult [13,14].

Furthermore, it is important to keep in mind that older people are at greater risk of malnutrition or sarcopenia with caloric restriction, causing low adherence to fasting situations and even medical contraindications following certain dietary approaches; hence, the personalization of dietary interventions according to age and sex should be individualized with the idea of preventing these situations and thus could maximize benefits and mitigate risks, particularly those associated with malnutrition or muscle mass loss in elderly populations, or could facilitate the completion of the proposed dietary treatment [7].

5. Conclusions

The findings analyzed in this study indicate that the dietary strategies reviewed (FMD, TRF, and PAAR) can mitigate the effects of aging by influencing metabolic pathways such as mTOR, IGF-1, and AMPK, promoting autophagy and reducing inflammation. These interventions are particularly relevant when metabolic imbalances such as obesity are present, as chronic insulin resistance and the inflammatory state characteristic of obesity exacerbate aging-related dysfunction.

Fasting-mimicking diets (FMDs) have demonstrated benefits in reducing visceral fat and improving insulin sensitivity, though long-term adherence remains a challenge. Time-restricted feeding (TRF) has fewer compliance barriers and regulates circadian rhythms, showing additional positive effects on circulating lipids in individuals with overweight, obesity, and metabolic syndrome. Protein and amino acid restriction (PAAR) provides longevity-associated benefits and inflammation modulation, though it requires individualized implementation in older adults to prevent sarcopenia.

In the clinical setting, it is essential to adapt each strategy to an individual’s age, metabolic status, and comorbidities to maximize benefits and minimize risks. Similarly, nutritional education and healthcare support are crucial in promoting adherence and long-term success. Although current findings are promising—especially in animal models and short-term human trials—evidence for actual lifespan extension in humans remains limited. Therefore, more long-term and comparative clinical trials are needed to better evaluate the combined impact of these diets on health span, quality of life, and the prevention of chronic diseases in aging and metabolically impaired populations. Overall, the personalized combination of these dietary practices, together with other nutritional and lifestyle interventions, represents a promising approach to delay aging-related complications and improve quality of life, particularly in individuals with excess adiposity and age-related metabolic dysfunction.

Future Research

Although the current evidence is strong in animal models and short-term human studies, its long-term applicability remains limited. Future research should focus on the following:

• Long-term clinical trials that simultaneously analyze the effects on life expectancy and quality of life, as well as the incidence rates of chronic diseases in individuals with and without obesity. A potential study could involve older adults with obesity and metabolic syndrome, assessing the evolution of inflammation biomarkers, autophagy, and insulin sensitivity under FMD, TRF, and PAAR protocols. These trials should be designed to yield both statistically and clinically significant outcomes.
• Differentiation by age groups and sex to determine whether the impact of each dietary strategy varies depending on life stage and hormonal profile. For example, a study in postmenopausal women could evaluate whether methionine and BCAA restriction enhances metabolic flexibility and reduces the risk of sarcopenia.
• An evaluation of the gut microbiota and its evolution in response to dietary interventions, given its key role in metabolism regulation and chronic inflammation. A human study could compare the microbiota composition before and after 12 weeks of TRF, FMD, or PAAR, assessing changes in key metabolites, their relationship with longevity, and the incidence of age-related diseases. Given its role as a key modulator of immune and metabolic responses, understanding microbiota dynamics may clarify individual variability in response to dietary strategies.
• Design of combined dietary protocols (e.g., TRE + PAAR) to determine synergies that improve adherence and metabolic control, particularly in obese populations. One possible study could analyze pre-diabetic patients undergoing TRF or FMD with a low-methionine diet to assess improvements in insulin sensitivity and low-grade inflammation. Such combined approaches may enhance clinical adherence and optimize therapeutic outcomes in metabolic disorders.
• Personalization based on biomarkers (lipid profile, leptin, adiponectin levels, or inflammation markers) to identify individuals with a higher probability of a favorable response. An example could be a study analyzing the relationship between baseline IGF-1 levels and the response to intermittent caloric restriction in individuals with obesity and insulin resistance. In addition to classical biomarkers, future studies could explore the relevance of epigenetic markers and inflammatory load to personalize dietary interventions.