Exercise and physical activity have a profound influence on the cardiovascular (CV) system, and this plays a significant role in promoting longevity. Engaging in regular exercise and physical activity is recognized for its ability to reduce the risk of CV disease factors, including high blood pressure, elevated cholesterol levels, type 2 diabetes, and obesity, implying that such activities may contribute to preventing the accumulation of plaque in the blood vessels leading to atherosclerosis (Tian and Meng, 2019). Additionally, exercise and physical activity have direct positive effects on the structure and function of blood vessels and the heart, including cardiac preconditioning and improved autonomic balance (Fiuza-Luces et al., 2018). VO2 max, a measure of maximal oxygen consumption during intense exercise, is widely regarded as a strong predictor of longevity. Higher levels of VO2 max are associated with improved CV health, increased aerobic fitness, and a reduced risk of chronic diseases, contributing to a longer and healthier life (Letnes et al., 2023). One of the mechanisms by which exercise contributes to CV benefits is by improving the function of endothelial progenitor cells, which help repair damage to blood vessel linings (D’Onofrio et al., 2023). As people age, these cells tend to work less effectively, but exercise can enhance their function. Furthermore, exercise reduces oxidative stress in blood vessels associated with aging, enhances endothelial function, and boosts markers of blood vessel repair and the formation of new blood vessels (D’Onofrio et al., 2023). Epidemiological studies show that being physically active is associated with a reduced risk of death, whether someone has or does not have CV disease, with more significance for individuals with CV disease (Jeong et al., 2019). A systematic review and meta-analysis that included data from 21 studies and 159.352 CV disease patients showed that high cardiorespiratory fitness was associated with a 73% reduction in CV mortality risk and a 58% reduction in all-cause mortality risk (Ezzatvar et al., 2021). Furthermore, another meta-analysis that examined the relationship between step count and all-cause mortality or CV events found that an increase in 1000-step/day count was associated with a 23% reduction in all-cause mortality risk (Banach et al., 2023).

The musculoskeletal system is composed of muscles, bones, joints, ligaments, tendons, fascia, and neuromuscular interface, which together support a person’s stability, mobility, and metabolism. Muscles are metabolically active organs that contribute to the proper functioning of insulin, glucose regulation, fatty acid oxidation, and other metabolic functions (Baskin et al., 2015). During aging, the musculoskeletal system structure and functions decline, which results in sarcopenia (loss of muscle mass, 3%–8% per decade after age 30, with an increased rate of decline after age 60), loss of muscle power and strength as well as a decrease in muscle flexibility and balance (D’Onofrio et al., 2023). Several age-related mechanisms are thought to be associated with sarcopenia, such as the decline in mitochondrial density and instability of mitochondrial DNA, dysregulation of the tissue renin-angiotensin system, as well as failure of adaptive responses to contractile activity is suspected to play a role in muscle mass loss, such as the ability to clear reactive oxygen species (Larsson et al., 2019; Saravi et al., 2021). Additionally, age-related changes include an increase in fat mass, a decline in basal metabolic rate (2%–3% per decade), and a decrease in bone mineral density (1%–3%/year) (Keys et al., 1973; Westcott, 2012). The aging process of the musculoskeletal system can be even more accelerated by the presence of other conditions and/or diseases, such as insulin resistance, diabetes, obesity, and chronic inflammation (Carapeto and Aguayo-Mazzucato, 2021).

There is wide evidence about the contribution of exercise, mainly strength and resistance training, in slowing the aging process of the musculoskeletal system. Resistance training promotes muscle growth and improves muscle quality by stimulating the motor unit, leading to the enlargement of muscle fibers, enhanced neuromuscular coordination, and increased strength. This is largely regulated by insulin, available amino acids, and the mTOR pathway (Atherton and Smith, 2012). Notably, there are only minimal reductions in muscle mass with age in the athletes (Wroblewski et al., 2011). Furthermore, chronically, the creation of higher muscle mass “speeds” metabolism by raising basal metabolic rate allowing individuals to burn more calories, which is important for managing weight, obesity and diabetes (D’Onofrio et al., 2023). One mechanism of exercise reducing sarcopenia is by decreasing inflammation and increasing anabolism and protein synthesis. Furthermore, activation of coactivators that are key regulators of mitochondrial biogenesis (e.g., PGC-1α), improves mitochondrial remodeling, muscle endurance, and enhanced balance and motor coordination in animal models (D’Onofrio et al., 2023).

Furthermore, resistance training is a long-term strategy for treating osteoporosis and age-related loss in bone mineral density. There is evidence to support that exercise leads to significant changes in bone mineral density, decreases in total body fat mass, and increases in total body lean mass (Santos et al., 2017). Resistance training also prevents fall risk among older adults (Carter et al., 2002). One explanation could be that weight-bearing activities can induce bone formation by delaying telomere shortening and modifying DNA methylation (Carter et al., 2002).

Immunosenescence is the gradual deterioration of the immune system with age, characterized by significant shifts in the balance of leukocyte subsets. Regular exercise may help slow down the immunosenescence process by promoting the health and function of immune cells (Weyh et al., 2020). For example, long-term exercise from adulthood to old age induces anti-inflammatory effects, which is indicated by decreased level of inflammatory biomarkers, including white blood cell and neutrophil counts, IL-6, IL-10, IL-1 receptor antagonist, and soluble tumor necrosis factor receptor-1 (Moore et al., 2012).

Furthermore, aging weakens the immune system’s ability to fight infections, including viruses and bacteria, and exercises emerge as a safe and cost-effective strategy for combating infectious diseases. For example, it was shown that a regular program of aerobic exercise (intensity of 55%, 80% VO2max) helped to reduce the risk of coronavirus disease (COVID-19) by increasing immunological biomarkers, such as circulating lymphocytes, leukocytes, monocytes, and neutrophils (Abdelbasset, 2020; Alawna et al., 2020; Mohammed et al., 2021).

Moreover, regular exercise profoundly affects the endocrine system, playing a role in longevity by regulating hormones and diminishing chronic inflammation. Notably, exercise positively influences insulin interactions, enhancing its efficiency in transporting glucose into muscle cells. This process helps regulate blood sugar levels, reducing the reliance on excessive insulin production and decreasing insulin resistance (Yaribeygi et al., 2019).

In recent years, gut microbiota and intestinal health have been described as important players shaping overall human health, and gut dysbiosis has been regarded as a new hallmark of aging (López-Otín et al., 2023). The beneficial effect of exercise on gut microbiota is contributed by several mechanisms, including an increase in bacterial diversity (usually associated with favorable health outcomes), an increase in fecal short chain fatty acids (SCFA), an increase in the proportion of health-promoting bacterial species (e.g., Faecalibacterium prausnitzii, and Akkermansia muciniphila), and a decrease of obesity and metabolic diseases-related bacteria (e.g., Eubacterium rectale and Clostridium coccoidea) (Estaki et al., 2016; Bressa et al., 2017; Allen et al., 2018; Yuan et al., 2022). A systematic review showed that aerobic training (≥2 weeks) of at least 60 min in non-athlete subjects increased diversity indexes of gut microbiota (Dziewiecka et al., 2022). Also, it was shown that athletes usually have more diverse microbiota, a higher abundance of SCFA, and lactic acid-producing bacteria. Additionally, the study showed that for inducing the changes in gut microbiota not only dose and mode of exercises are important, but also the patterns such as breaks in sedentary time and avoidance of long periods of inactivity in daily life (Dziewiecka et al., 2022).

Consistent exercise could enhance cognitive functions and protect against the onset of cognitive decline or dementia. In a study of 900 older individuals engaging in resistance training exercises, an increase in muscle strength correlated with a remarkable 43% decrease in the risk of developing Alzheimer’s disease and a 33% reduction in the risk of mild cognitive impairments (Boyle et al., 2009), exercise is associated with psychological benefits, including more positive mood, reduction in depression and anxiety, higher self-esteem, and a sense of vigor (Gordon et al., 2017; Amiri, 2023). In a comprehensive meta-analysis encompassing 33 randomized clinical trials and 1877 participants, resistance training demonstrated a significant reduction in symptoms of depression across various baseline health statuses, indicating a moderate effect size (Gordon et al., 2018).

The human body functions as a unified system. Therefore, a single exercise intervention, such as resistance training, can yield multiple benefits for various organs and systems within the body. For example, muscle, which belongs to the musculoskeletal system, is also an endocrine organ, producing and releasing signaling molecules (myokines) into the bloodstream in response to muscle contractions and exercise. Myokines may directly enhance CV health by improving endothelial cell function, protecting against endothelial injury and atherosclerosis, and positively impacting myocardial contractility (Pedersen and Febbraio, 2012). Furthermore, the effects of exercise on muscle health may play an important role in bone health and other organs and tissues. For example, the protein irisin secreted by skeletal muscle can regulate bone remodeling but also affects adipose tissue, cholesterol metabolism, inflammation, glucose tolerance, and cognitive function (D’Onofrio et al., 2023). Also, the beneficial effect of exercise on muscle mass is known to help in the management of insulin resistance, which is a prediabetes state, thus preventing type 2 diabetes by having the so-called “browning” effect of white adipose tissue and effect on cellular energetics through mitochondrial biogenesis (Weyh et al., 2020).

Further, regular exercise positively impacts the gut and produces systemic benefits. For example, exercise protects intestinal permeability, reducing the absorption of molecules like lipopolysaccharide (LPS) that contribute to systemic inflammation—another factor associated with CV disease, obesity, and yype 2 diabetes. This protective effect helps prevent the initiation of pro-inflammatory responses and the formation of macrophage cells, which are early indicators of atherosclerotic lesions (Yuan et al., 2022; D’Onofrio et al., 2023).

The evidence in previous sections clearly suggests that exercise and physical activity benefit human health and lifespan. Regarding guidelines and protocols, the scientific community generally accepts the World Health Organization (WHO) protocols.

According to the WHO, for adults (18–64 years old), physical activity is regarded as critical for reducing all-cause mortality; managing weight; reducing adverse events; improving cognitive outcomes and mental health; as well as reducing the incidence of type 2 diabetes, CV diseases, and cancer (Bull et al., 2020). The recommended weekly activity is 150–300 min of moderate-intensity aerobic exercise or 75–150 min of vigorous-intensity activity, with higher duration and intensity enhancing CV and metabolic effects. A recent study confirmed that adhering to these guidelines reduced the risk of early death by up to 25% and that exceeding recommendations by 2–4 times further lowered the risk by an additional 4%–13% (Lee et al., 2022). Aerobic physical activity beyond 300 min/week of moderate intensity or 150 min/week of vigorous intensity is conditionally beneficial, as the optimal threshold remains unclear. As early as 1986, studies reported a reverse J-shaped association between exercise (e.g., walking, stair climbing, sports play) and all-cause mortality. This curve suggests a dose-dependent relationship between exercise and longevity until an optimal threshold is surpassed, beyond which benefits may decline (O’Keefe et al., 2020). Some research also suggests that prolonged exercises exceeding 10 h/week might have undesirable effects (O’Keefe et al., 2020).

In children (5–17 years old), the WHO underscores the importance of physical activity for bone health and the development of prosocial behavior, both important factors to longevity. Physical activity is recommended for older adults to prevent falls, fall-related injuries, and declines in bone health and functional ability. In addition to aerobic activities, adults 65 years of age and older are advised to engage in multicomponent physical activities, encompassing functional balance and strength training at a moderate or higher intensity for at least 3 days a week (Bull et al., 2020).

These recommendations are primarily derived from observational studies. To establish more precise guidelines, the scientific community should: (i) Establish protocols for conducting high-quality randomized controlled trials (RCT); (ii) Define universal cut-points for classifying different intensity intervals. Intensity is measured using metrics like %VO2max (% of maximal oxygen consumption) or %VO2R (% oxygen uptake reserve), with various cut-points in studies. Other physiological variables (maximum heart rate, heart rate reserve, ventilatory or lactate thresholds) may also be used to identify intensity zones; (iii) Develop more accurate technologies (e.g., smartwatch tools); and foster a consensus among researchers on classifying individuals into different intensity levels.

Despite these challenges, the overall evidence implicate the following: Physical activity and exercise, as a dynamic and energy-intensive activity, impart a plethora of benefits to the CV, musculoskeletal, immune, endocrine systems, and gastrointestinal systems, all contributing to longevity and overall wellbeing. It is recommended that individuals of all ages should adhere to the minimum guidelines for physical activity to promote longevity. Starting from an early age, consistent exercise should be integrated into daily routines. Middle-aged and older individuals, if not already engaged, should begin incorporating exercise.

Caloric restriction (CR) is the most robust and the best studied dietary intervention for its effect on promoting longevity. Already in 1935, it was noted that CR could prolong the lifespan in rats, and since then, scientific evidence showing the positive benefits of CR both in animal models and in humans has been accumulating (McDonald and Ramsey, 2010). CR includes reducing calorie intake over a given period while maintaining essential nutrients. It involves consuming fewer calories than what is considered the standard daily energy requirement for an individual’s sex, age, and activity level (Dorling et al., 2020). Typically, in humans, the most studied is 10%–25% CR per day. CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Energy) I and II were the first controlled clinical trials to assess the efficacy, safety, and feasibility of a 6–12 months CR diet. CALERIE I trial showed that CR improves biomarkers associated with aging and age-related diseases, including a reduction in markers of energy metabolism metabolic adaptation and improvements in many CV risk factors. This trial also showed that a moderate 12%–18% CR is safe and feasible, not compromising quality of life (Rickman et al., 2011).

CALERIE II study aimed to explore the effects of prolonged CR durations related to an organism’s lifespan and establish if CR-induced alterations have an effect beyond the initial period of weight loss. The study showed that after the period of 2 years, an average of 11.7% CR could improve longevity and decelerate primary aging by decreasing the mass-specific metabolic rate and total energy expenditure. By lowering energy expenditure there is a decrease in the production of reactive oxygen species and DNA damages, proteins, and lipids crucial for normal cellular function. Furthermore, healthy, and young participants significantly improved body composition, inflammatory and cardiometabolic risk biomarkers, and aerobic fitness (Dorling et al., 2021). This suggests that CR slows secondary aging by improving numerous markers of disease risks.

The benefits of CR are also confirmed in the Biosphere 2 experiment that involved individuals who lived in a closed ecological system for 2 years. Although not explicitly intended for the investigation of CR, the circumstances within a closed ecological setting naturally induced CR due to the limited food resources. The study provided insights into the positive effects of CR on human physiology, including changes in metabolism and body weight (Walford et al., 1992).

Various studies in animal models and humans showed that CR activates multiple molecular pathways that promote genome stability, proteostasis, stress resistance, and stem cell function mainly by inhibiting key nutrient-sensing and inflammatory pathways (Most et al., 2017; Kökten et al., 2021). CR involves multiple neural, tissue-specific, cell-autonomous, and systemic mechanisms that are the sum of various metabolic, transcriptional, proteomic, and even microbiota alterations (Dorling et al., 2020). Furthermore, as changes occur at varying levels and in different pathways that result in enhancement of neurogenesis, synaptic plasticity, brain structure, and function, CR has also been shown to be beneficial for cognitive protection and improvement of slowing down the progression of cognitive age-related diseases such as Alzheimer’s disease (Van Cauwenberghe et al., 2016; Alharbi et al., 2023; Rahmani et al., 2023).

While considerable beneficial evidence exists in both human and animal studies supporting CR, certain challenges may arise during prolonged CR. Such challenges include decreased adherence, feelings of hunger, weight regain, and potential loss of lean mass and bone density (Hofer et al., 2022). However, data on these outcomes are inconsistent, necessitating further research. These effects can be mitigated with careful consideration of intervention duration, nutrient composition, and complementary exercises. Individual responses to CR, optimal levels, and durations require a personalized approach. In the current clinical practice, CR is recommended for weight management. Nevertheless, based on scientific evidence from pre-clinical and human studies, future clinical applications may extend to recommending CR for specific pathological conditions such as CV diseases, metabolic disorders, and cancers.

Unlike CR, where there is a constant reduction of meal size and/or calorie intake during the meals, intermediate fasting (IF) is characterized by temporal dietary restriction by skipping one or more consecutive meals (Varady et al., 2022).

There are various types of IF differing in rhythmic or arhythmic regimens, including Alternate Day Fasting (ADF), individual fasts every other day, without any calorie intake or if mildly performed, 25% of baseline calorie intake is permitted; Periodic Fasting (PF) where individual can follow different schemes such as so-called 5:2, where calories are restricted in 2 days a week to a minimal level; Time-Restricted Eating (TRE) where individual skip a specific meal (breakfast or dinner), or by consuming the meals into a narrow time window. The detailed health outcomes of different IF regimes through different studies are very well reviewed and described by Dorling and coauthors (2020).

In general, alike in CR, IF decreases markers of systemic inflammation (that, among other reasons, may be due to the chronic excess calorie consumption) and oxidative stress that are two important drivers of aging and metabolic diseases such as T2D, insulin resistance (Meydani et al., 2016; Stekovic et al., 2019). Both IF and CR improve the blood lipid profile and other relevant factors for CV disease (Most et al., 2017; Trepanowski et al., 2018; De Cabo and Mattson, 2019), animal models of neurodegenerative diseases, such as Alzheimer’s IF and CR, were able to delay the progression of phenotypes of the disease (Mattson et al., 2017). Marinac et al. (2016) showed that more than 13 h of fasting during nighttime is associated with reduced breast cancer risk. Also, a recent systematic review concluded that different IF regimes could positively impact the diversity and abundance of gut microbiota (Pérez-Gerdel et al., 2023).

Regarding the mechanisms, prolonged periods of fasting state are characterized by a metabolic switch from glucose dependency to elevation of lipid metabolism, including free fatty acid usage and production of ketone bodies in the liver (Hofer et al., 2022). This, in turn, stimulates adaptive processes, improving body composition and physiological function. The process of metabolic switching usually starts after 12–36 h of food abstinence, but this depends on many factors, such as baseline hepatic glycogen storage and activity levels. Cells sense nutrient levels and adjust their behavior through various interconnected pathways, including activation of AMPK and shutdown of mTOR pathway and engagement of various transcription factors (e.g., FOXOs, PGC-1α), resulting in activation of autophagy, mitophagy DNA repair, and oxidative stress defense (Hofer et al., 2022).

Other types of fasting or CR-mimicking interventions include various dietary interventions aiming to elicit some CR-like molecular and physiological effects, such as fasting-mimicking diets, low-carbohydrate/fat diets, or ketogenic diets (Brandhorst et al., 2015; Boison, 2017; Kim, 2021).

Within plant-based diets various dietary patterns are focusing on plant-based food sources with little or no consumption of animal products, thus up to date there is no one universal definition for plant-based foods. The most practiced plant-based diets include vegetarian diet (diet that excludes meat and poultry), and vegan diet (diet that excludes any type of food derived from animals, e.g., meat, dairy products, honey).

In recent years, there has been an increased interest in potential longevity-promoting pathways associated with plant-based diets. These diets, characterized by restricted protein intake, amino acids such as branched-chain amino acids (BCAA) and methionine, share the same mechanisms with the mechanisms linked to health improvement and longevity observed in CR diets (Herpich et al., 2022). The Adventist Health Study 2 (AHS-2) with 96.000 adults found that ovo-lacto-vegetarian diets (includes eggs, dairy, and honey, but not fish) were linked to lower all-cause mortality, BMI, and reduced risks of diabetes, hypertension, and certain cancers (Orlich et al., 2013). Vegan diets showed even lower risks for CV mortality, obesity, hypertension, and type 2 diabetes. Herpich and colleagues (2022) conducted a comprehensive meta-study on plant-based diets, revealing diverse outcomes regarding mortality reduction and health improvements. These findings are dependent on the inherent variations among plant-based diet types and are not universally applicable across different plant-based diet categories. Future large-scale human studies are warranted to understand better the specific mechanisms influencing longevity. Nevertheless, well-planned plant-based diets provide metabolic, CV, and intestinal benefits, ultimately contributing to an extended health span and potentially an increased life span.

The Mediterranean diet (MedDiet) reflects dietary patterns traditionally observed in civilizations cultivating olives in the Mediterranean region, particularly in southern Italy, Greece, and Crete. Key features of the MedDiet include elevated consumption of virgin and extra virgin olive oil as the primary fat source, along with a substantial intake of vegetables, legumes, fruits, minimally refined cereals, nuts, seeds, and fresh, locally sourced, seasonal, and minimally processed foods. Also, the diet involves limited or moderate intake of dairy products, fish, and poultry, while red meat and sweets are consumed sparingly. Additionally, moderate wine consumption is included during meals Andreo-López et al., 2023).

MedDiet has been associated with low rates of age-related diseases, mainly CV, metabolic, neurodegenerative, and oncological conditions, contributing to an extended life expectancy (Martinez-Gonzalez and Martin-Calvo, 2016). The constituents of the MedDiet, such as essential omega-3 and 6 fatty acids, polyphenols, fibers, and vitamins, are reported to positively impact the molecular pathways associated with all recognized hallmarks of aging (Martinez-Gonzalez and Martin-Calvo, 2016; Campanella et al., 2021). Future studies should provide a better understanding of the mechanism of action of MedDiet on aging as a whole. However, the benefits of MedDiet constituents on human health present robust evidence; thus, this diet could be practiced delaying age-related diseases and maintain good health.

This diet is based on the pillars from previously mentioned findings of the life span research in model organisms and clinical studies (Longo and Anderson, 2022). It is developed by biochemist Valter Longo, Ph. D, and below are the main characteristics of this diet:

• Periodic fasting or calorie restriction have a central role;

Additionally, the author emphasizes the necessity of tailoring the diet to age, sex, and health status to prevent malnutrition. Ongoing research on the longevity diet persists, with the scientific community actively investigating its potential benefits for health and longevity.

Blue zones are the geographical areas characterized by exceptionally long-lived populations. They include the island of Ikaria in Greece, the island of Okinawa in Japan, the mountain area of Sardinia in Italy, and the peninsula of Nicoya in Costa Rica. Their diets share some common patterns with all previously described diets, such as predominant consumption of plant-based foods, moderate protein intake, intake of healthy fats, and caloric moderation (Kreouzi et al., 2022). Since these populations have been long-lived, researchers started investigating the Blue Zones’ eating regimes.

Nevertheless, there is a common tendency to assume that the mere documentation of a diet within a long-lived population automatically establishes it as a causal factor for the population’s longevity. Such a claim requires substantiation and should be supported by evidence. It is important to note that diet is just one component of the broader lifestyle factors associated with longevity in Blue Zones. Other factors include physical activity, strong social connections, a sense of purpose, and a low-stress lifestyle, which also confirms that multiple aspects of live should be satisfied for longevity.

Additionally, recently significant question about the validity of Blue Zones raised, especially one by Dr Saule Newman, an Oxford researcher (Newman, 2019). He argues that longevity observed in these regions may be due to inaccurate record-keeping and age exaggeration rather than from unique lifestyle factors, as well as historical gaps in vital records leading to overrepresentation of centenarians. His analysis calls for a more cautious interpretation of Blue Zones, where more scientific studies are needed to verify these claims and clarify whether the Blue Zone lifestyle truly accounts for extended lifespans.

Fisetin is a flavonoid found in various fruits and vegetables, such as strawberries, apples, onions, and cucumbers. Fisetin is known for its antioxidant, anti-inflammatory, anticancer, and neuroprotective properties. The key mechanism through which fisetin promotes longevity is its senolytic activity (Khan et al., 2013). It means that fisetin can remove accumulated senescence cells from the body that damage neighboring cells and tissues, which induces inflammatory damage and leads to various age-related diseases. When tested together with other flavonoids in mice and in senescent human fibroblasts, fisetin showed to be the most potent senolytic (Yousefzadeh et al., 2018). In model organisms, fisetin showed the ability to prolong lifespan, particularly 13% in mice, 23% in Drosophila, and 55% in Saccharomyces cerevisiae (Khan et al., 2013; Yousefzadeh et al., 2018). Furthermore, it showed the potential to reduce neurodegenerative diseases and prevent certain types of cancer (Khan et al., 2013). Given Fisetin’s potential in combating age-related diseases, ongoing clinical trials are exploring its efficacy against inflammation, CV diseases, certain cancers, and in reducing mortality and long-term complications associated with COVID-19.

Most of the studies used 20–500 mg per day, with no significant adverse effects reported; also available supplements on the market contain fisetin dosages within this range.

Quercetin is another flavonoid compound found in many fruits, vegetables, and grains. Quercetin is known for its cardioprotective, anti-inflammatory, antiviral properties, and anti-cancerogenic activities (Aghababaei and Hadidi, 2023) all important for longevity. Laboratory aging models demonstrate that quercetin increases lifespan by up to 60% (Belinha et al., 2007). In humans, quercetin showed its potential to protect against CV diseases (Egert et al., 2009; Pfeuffer et al., 2013). In combination with dasatinib, it can selectively decrease the number of naturally occurring senescent cells, as well as reduce adipose tissue inflammation, and improve systemic metabolic function in old age (Zhu et al., 2016; Islam et al., 2023). Furthermore, intermittent oral administration of these two compounds reduced mice mortality hazard by up to 65% (Xu et al., 2018).

Dosages of quercetin up to 1 g are well tolerated. It is suggested to administer quercetin supplements with other bioflavonoids such as resveratrol, genistein, or green tea catechins to increase bioavailability. The best bioavailability form showed to be dihydrate, followed by glycosides, aglycone, and rutinoside (Jaffe and Mani, 2018).

Rapamycin, a macrolide compound derived from Streptomyces hygroscopicus, has attracted attention not only for its effective immunosuppressive properties but also for its impact on longevity, as it is the first pharmacological compound shown to extend lifespan in mammals (Harrison et al., 2009; Ehninger et al., 2014; Arriola et al., 2016). Rapamycin exerts its anti-proliferative properties by inhibiting the mammalian target of rapamycin (mTOR) pathway, which is a central regulator of cellular growth and it is known for its key role in the aging process. Mechanistically speaking, it acts on inducing autophagy and suppressing protein synthesis (Li et al., 2016). Inhibition of mTOR has been correlated with lifespan extension in mice and other organisms (Lamming et al., 2013). The ability of rapamycin to extend lifespan has prompted extensive research into its potential as an anti-aging intervention. Although the translational implications for human longevity are still under investigation, its promising therapeutic applications are supported by robust preclinical data (Kulkarni et al., 2022).

Metformin, a widely prescribed antidiabetic medication known for its broad efficacy in managing glucose metabolism, is emerging as one of the most promising gerotherapeutic drugs due to its potential role in extending lifespan. The primary mechanism of action involves the regulation of cellular energy metabolism through the activation of adenosine monophosphate-activated protein kinase (AMPK) (Cho et al., 2015), reduction in insulin levels (Liu et al., 2022), and modulation of mitochondrial function (Konopka et al., 2019). Metformin’s regulation of protein synthesis in mitochondria, coupled with the activation of AMPK, influences various cellular processes with implications for aging and longevity, including promoting autophagy.

In addition to its pivotal role in glycemic control, metformin has been associated with beneficial effects on diverse health outcomes. Clinical and observational studies have linked metformin to positive impacts on cardiovascular disease, Alzheimer’s disease in diabetic patients (Novelle et al., 2016; Campbell et al., 2017; Mohammed et al., 2021), and reduced mortality (Campbell et al., 2018).

The TAME (Targeting Aging with MEtformin) study is a clinical trial exploring metformin’s potential as an intervention to address aging and age-related diseases, testing the concept of “geroprotection.” This novel approach aims to delay the onset of multiple age-related diseases and extend the health span. Involving a diverse group of participants aged 65 to 79 with or at risk for age-related diseases, the study utilizes a randomized, double-blind, placebo-controlled design to rigorously evaluate metformin’s geroprotective effects (Barzilai et al., 2016).

CR - as mentioned previously in this review, has long been associated with enhanced longevity and delayed aging across various organisms, primates and mice included (Fontana et al., 2010; Mattison et al., 2017; Xie et al., 2022). However, the same degree of beneficial effects has not been observed in humans. Additionally, the metabolic and cellular adaptations induced by CR pose challenges for its practical application in everyday life. In response, the concept of caloric restriction mimetics (CRMs) has emerged, aiming to replicate the beneficial effects of CR without necessitating stringent dietary regimens.

CRMs are widely present in food and function by targeting key cellular pathways implicated in the response to reduced caloric intake. This includes the activation of sirtuins, AMPK, and mTOR pathways, all of which play crucial roles in cellular metabolism, energy sensing, and stress response (Madeo et al., 2019).

Several compounds have garnered attention as potential CRMs; Resveratrol, spermidine, aspirin, quercetin, curcumin, and nicotinamide are among the most investigated molecules. Despite the optimism surrounding these compounds, challenges persist, including concerns about safety, specificity, and efficacy in humans, as they have been tested in small-case studies (Hofer et al., 2022; Hofer et al., 2022).

Systemic chronic inflammation, often referred to as ‘inflammaging,’ is known to exacerbate the hallmarks of aging and to significantly contribute to the progression of age-related diseases (Li Z. et al., 2023). This ongoing inflammatory state is the result from the accumulation of cellular damage, immune system dysregulation, and the presence of pro-inflammatory factors over time (López-Otín et al., 2023).

Managing inflammaging is an attractive target for improving health in old age. In addition to the aforementioned caloric restriction (CR) mimetics, senolytics have shown promise in reducing age-related conditions such as sarcopenia, cataracts, vascular pathology, and cognitive decline in animal models (Baker et al., 2011; Roos et al., 2016; Ogrodnik et al., 2021), such as dasatinib and quercetin, work by eliminating senescent cells, which reduces the production of pro-inflammatory cytokines including TNFα, IL-6, and IL-8, as well as alleviating activation of signaling pathways such as NF-κB and JAK/STAT3—key contributors to chronic inflammation (Dugan et al., 2023).

Despite these promising results, questions remain about the duration of benefits and potential adverse effects of long-term senolytic use, which must be addressed through clinical trials before broad implementation.

There is large evidence data indicating that sauna bathing has reduces the risk of cardiovascular diseases (CVD), neurodegenerative diseases, and pulmonary diseases, as well as pain relief properties (Kunutsor et al., 2018a; Ahokas et al., 2023). Sauna is form of passive thermal therapy by exposure to high environmental temperature from 80°C to 100°C for a brief period, ranging from 5–20 min depending on the individual needs (Kukkonen-Harjula and Kauppinen, 2006). A number of studies have assessed the effect of sauna over cardiovascular conditions, including hypertension, ischemic stroke and CVD mortality (Zaccardi et al., 2017; Kunutsor et al., 2018b; 2018a). A few longitudinal studies assessed sauna bating and CVD mortality over 24 years, concluding a 47% risk reduction for hypertension and 62% risk reduction for stroke in individuals who practiced frequent sauna baths (Zaccardi et al., 2017; Kunutsor et al., 2018b). Additionally, sauna bathing has been associated with 65% reduced risk of neurodegenerative diseases such as Alzheimer’s and dementia (Laukkanen et al., 2017). Application of local heat therapy and sauna is shown to promote muscular vascularity and improve muscle soreness (Heinonen et al., 2011; Ahokas et al., 2023). The sauna has a pleiotropic effect that has been shown to increase high-density lipoprotein cholesterol (HDL-C), decrease low density lipoprotein cholesterol (LDL-C), to have antioxidant effect and reduce reactive oxygen species, improves endothelial function and immune support (Laukkanen et al., 2018).

Alternative method to sauna therapy is infrared sauna that uses infrared heaters to emit infrared light that is absorbed by the skin and underlying tissues, creating heat within the body. The heat raises the core temperature, inducing a state of therapeutic warmth and sweating response. Typically, infrared sauna has lower temperature and lower level of humidity. Infrared sauna has a pain-relieving properties that help treat muscle soreness, stiffness and chronic fatigue (Oosterveld et al., 2009; Ahokas et al., 2023).

Intermittent changes of sauna bathing and cooling with cold water immersion therapy is beneficial with regards to cardiorespiratory fitness, endocrine systema and thermoregulation (Podstawski et al., 2021; Søberg et al., 2021). Cold water immersion consists of body exposure to cold water between 0°C and 10°C for a short period of time. Alternative method is cryotherapy chambers, where the cold exposure happens in a controlled cold environment using liquid nitrogen or electric cooling system. Cryo chambers create much lower temperature up to −129°C. Brief immersion in cold water elicits cold shock response, activation of the sympathetic nervous system and improved thermogenesis (Søberg et al., 2021). There has been some adverse effect associated with drastic temperature changes such as ventricular and atrial arrythmia in some individuals with CVD (Schmid et al., 2009). The acute thermodynamic stress that the body endures during hot and cold therapy, stimulates the immune function, and improves innate immunity (Brazaitis et al., 2014). While the effect of hot and cold therapy is known for optimizing physical health, there are also evidences supporting the beneficial effect of cod water immersion or cryo chambers on cognitive health, improved focus, mood enhancement and depression (Miller et al., 2011; Rymaszewska et al., 2021; Kelly and Bird, 2022).

Red light therapy, also known as photo biomodulation or low-level laser therapy, involves the use of red or near-infrared light to stimulate various cellular processes in the body (de Freitas and Hamblin, 2016). A proposed mechanism of action is that the photons dissociate inhibitory nitric oxide from the enzyme, leading to an increase in electron transport, mitochondrial membrane potential and ATP production. That leads to activation of transcription factors related to protein synthesis, and cell proliferation (de Freitas and Hamblin, 2016). Red light therapy in different wavelengths is used clinically in several directions, most successfully to treat skin disorders such as scar tissue, acne, and wrinkles (Nam et al., 2017; Santiago et al., 2022). Near-infrared light therapy increases collagen production in the skin that improves the firmness and elasticity of the skin layers and reduce inflammation and redness (Nam et al., 2017). Additional therapeutic benefits of longer wave lengths of red light have been investigating with regards to muscle recovery, joint pain relief and local inflammation (Wickenheisser et al., 2019; Ailioaie and Litscher, 2021; González-Muñoz et al., 2023).

IHHT training involves alternating cycles of adaptation in normobaric hypoxia and then reoxygenation and hyperoxia. It is achieved by breathing hypoxic gas mixture through a mask in a controlled environment for few minutes in each cycle. The adaptation of episodes of hypoxia and hyperoxia is a powerful stress factor that triggers physiological reaction in the body and tissues, which improves the overall resilience of the organism (Rybnikova et al., 2020). IHHT enhances cardiac muscle resistance to hypoxia and improves myocardial function (Glazachev et al., 2017). Additionally, IHHT can affect metabolic health as it affect glucose metabolism, by improving glucose tolerance as well as symptoms of obesity and diabetes (De Groote et al., 2018). Similarly, IHHT has been shown to improve lipid profile in patients with already diagnosed metabolic syndrome, as well as improve their anti-inflammatory status (Afina et al., 2021). IHHT also has a direct effect on cognitive function and cerebral vascular health, due to improved hypoxia tolerance and improved protection of mitochondrial damage (Li et al., 2016; Rybnikova et al., 2022). Moreover, patients with already diagnosed mild cognitive impairment and Alzheimer’s diseases show improved cognitive test scores after IHHT (Serebrovska et al., 2019). Recent findings associate IHHT with telomere stabilization and protection form cellular senescence and apoptosis, which has a beneficial effect on age-related diseases (Tessema et al., 2022).

HBOT uses the power of 100% oxygen in environmental pressure higher than one absolute atmospheres (ATA) to promote healing and enhance overall wellbeing. A typical HBOT continue for approximately 90 min with some changes of ATA and breaks with normal air in between. There have been numerous clinical indications for using HBOT including for venous embolism, severe carbon monoxide poisoning, anemia, chronic osteomyelitis, and idiopathic sensorineural hearing loss (Kirby et al., 2019). Along with the obvious benefit of delivering more oxygen to the tissues, HBOT has beneficial effect on vascular health, hemoglobinopathies, improved circulation (Lindholm and Lundgren, 2009). HBOT has also been implicated as a great tool for improving metabolic health and glucose regulation by improving peripheral insulin sensitivity (Wilkinson et al., 2012). For the first time in humans, recent findings have shown that HBOT can modulate the pathophysiology of skin aging, by angiogenesis and facilitating senescent cells clearance (Hachmo et al., 2021). A randomized clinical trial demonstrated that HBOT induces cognitive enhancement, improved attention, processing speed and executive function in aging adults, causing regional changes in cerebral blood flow (Hadanny et al., 2020). Most promising evidence regarding HBOT is its significant effect on increasing telomere length and clearance of senescent cells in aging population (Hachmo et al., 2020).

IV therapy is an innovative solution to directly infuse the body with carefully curated blend of essential nutrients, vitamins, mineral and health-promoting compounds. By delivering the nutrients directly to the blood stream and bypassing the digestive tract allows quicker absorption. A recent Mendelian randomized study found that some antioxidants (β-carotene, lycopene and uric acid), vitamins (A, B6, B12, C, D and K1), and minerals (Ca, Mg, Cu) are causally related to the development of metabolic syndrome (Li and Song, 2023). IV therapies can compensate for these well-known relationships between deficient levels of micronutrients and age-related conditions. Typical IV therapy includes some amino acids, vitamin C, vitamins from group B, vitamin D, some minerals, nutraceuticals such as glutathione. Prolonged infusion of glutathione has been indicated to improve myocardial cells survival (Tanzilli et al., 2019). A personalized mix of different nutrients can be used to increase energy levels, improve the immune system, enhanced skin health.