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# Cold and longevity: Can cold exposure counteract aging?

Ayoub Boulares*, Hela Jdidi, Wafa Douzi

Laboratory Mobility, Aging & Exercise-ER20296 (MOVE), University of Poitiers, Faculty of Sport Sciences, STAPS, Poitiers, France

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## ARTICLE INFO

**Keywords:**

Cold exposure

Longevity

Aging

Environment

Temperature

## ABSTRACT

Aging is a multifaceted biological process characterized by a progressive decline in physiological functions and heightened vulnerability to diseases, shaped by genetic, environmental, and lifestyle factors. Among these, cold exposure has garnered interest for its potential anti-aging benefits. This review examines the impact of cold exposure on aging, focusing on key physiological processes such as inflammation, oxidative stress, metabolic regulation, and cardiovascular health. Cold exposure has been shown to reduce chronic inflammation, enhance antioxidant defenses, and improve metabolic health by activating brown adipose tissue. Furthermore, findings from hibernating mammals and model organisms suggest a connection between lower environmental temperatures and increased longevity. However, the potential long-term health risks of extended cold exposure, particularly in older adults, remain a significant concern. Epidemiological studies reveal increased rates of mortality and morbidity in populations living in cold climates, emphasizing the complexity of the relationship between cold exposure and aging. This review underscores the need for further research to elucidate the long-term effects of cold exposure on aging and to establish guidelines for leveraging its benefits while mitigating cold-induced risks.

## 1. Introduction

Aging is a complex, inevitable biological process marked by a gradual decline in physiological functions and an increased susceptibility to diseases. One of the key contributors to this decline is the cellular senescence, an irreversible arrest of cell division triggered by various stressors such as DNA damage, oxidative stress, and telomere shortening [1]. While cellular senescence initially serves as a tumor-suppressive mechanism, the accumulation of senescent cells over time promotes chronic inflammation, disrupts tissue homeostasis, and accelerates organismal aging [2]. This process is further influenced by a dynamic interplay of genetic, environmental, and lifestyle factors. While genetics significantly determine lifespan [3], environmental and lifestyle factors are equally crucial in shaping the aging process [4]. These factors include diet, physical activity, exposure to toxins, and overall health maintenance, all of which contribute to how individuals age and their susceptibility to age-related conditions. Among these, temperature modulation, especially cold exposure, has emerged as a promising area of research for its potential anti-aging benefits.

Although the longevity benefits of low temperatures were documented over a century ago [5], the precise mechanisms by which cold influences lifespan and healthspan are not fully understood. The

prevailing hypothesis suggests that cold-induced longevity is mainly attributed to a slowdown in the rate of biochemical reactions and metabolic processes, leading to reduced energy expenditure and a decelerated pace of physiological activities [6]. Recent research, however, has uncovered more intricate mechanisms through which cold exposure can extend lifespan and improve health [7,8].

Cold exposure has been shown to impact several key physiological processes related to aging. One of the major mechanisms is its ability to reduce chronic inflammation, a condition often referred to as “inflammaging” [9]. Chronic, low-grade inflammation is a hallmark of aging and is associated with the development of various age-related diseases, including cardiovascular diseases, diabetes, and neurodegenerative disorders [9,10]. It has been reported [11,12] that cold exposure can mitigate inflammation by modulating immune responses and reducing the production of pro-inflammatory cytokines in healthy individuals as well as patients with inflammatory diseases. These cytokines are typically elevated in chronic inflammation and are associated with various age-related diseases. By lowering their production, cold exposure may help decrease systemic inflammation.

Another significant aspect of aging is oxidative stress, which results from the accumulation of reactive oxygen species (ROS) that causes damage to cellular components and contributes to cellular aging and

<footnote>* Corresponding author.</footnote>

<footnote>E-mail address: ayoub.boulares@univ-poitiers.fr (A. Boulares).</footnote>
various diseases. The free radical theory of aging posits that oxidative stress is a major driver of the aging process [13]. Cold exposure has been shown to reduce oxidative stress and enhance the body's antioxidant defenses, thereby reducing inflammation and protecting cells from damage.

Metabolic regulation is also profoundly affected by cold exposure by increasing energy expenditure and altering metabolic pathways. Activating brown adipose tissue (BAT) through cold exposure increases energy expenditure and improves metabolic health [14]. This process enhances insulin sensitivity, promotes lipid metabolism, and helps to regulate glucose metabolism, thereby mitigating inflammatory responses associated with metabolic dysfunction. These metabolic pathways play a crucial role in maintaining overall health and longevity. Additionally, recent studies have also revealed that cold exposure can activate proteasomes through PA28γ/PSME3 pathway, enhancing protein degradation and reducing disease-related protein aggregation. This mechanism has been observed in both model organisms, such as *Caenorhabditis elegans*, and human cells, suggesting a conserved role of temperature reduction in promoting longevity and preventing neurodegenerative diseases [15].

Despite the promising short-term benefits of cold exposure, the long-term effects remain unclear. Epidemiological studies present a paradox: while short-term cold exposure seems to offer health benefits, populations living in high-altitude cold environments face an increased health risks, including higher mortality rates and a greater incidence of cardiovascular diseases [16,17]. This complexity underscores the need for further research to fully understand the relationship between cold exposure and aging.

This review aims to explore the potential of cold exposure to counteract aging. It explores the physiological responses to cold, the short-term benefits, and the long-term health risks of prolonged cold exposure. By examining current evidence and identifying knowledge gaps, this review seeks to provide a comprehensive understanding of how cold exposure impacts the aging process and its potential as an anti-aging intervention.

## 2. Environmental impacts on aging and longevity: insights from select hibernating mammals

Environmental factors play a crucial role in aging and longevity processes, with valuable insights gained from the study of hibernating mammals. These hibernators, such as certain species of bats, ground squirrels, and marmots, have demonstrated remarkable lifespans, living up to 9.8 times longer than their expected average lifespan [18]. This extended longevity is largely attributed to their ability to enter a state of hibernation, a state characterized by a reduction in metabolic rate and body temperature, which enhances survival and promotes longevity [18,19].

Research on poikilotherms, such as *Drosophila melanogaster* and *Caenorhabditis elegans*, has shown that moderate changes in environmental temperatures can substantially affect lifespan [20,21]. Specifically, lower temperatures are associated with longer lifespans, highlighting an inverse relationship between temperature and longevity. This phenomenon is not exclusive to poikilotherms; studies in homeotherms, like mice, also reveal that slight reductions in core body temperature can positively impact lifespan. For instance, mice with a core body temperature lowered by 0.2-0.5 °C exhibit increased longevity [22]. Furthermore, transgenic mice overexpressing uncoupling protein 2 (UCP2) in hypocretin neurons show a similar reduction in core body temperature, leading to an average lifespan increase of 12 % in males and 20 % in females when fed an ad libitum diet [23].

These findings suggest that the mechanisms associated with hibernation—such as lowered metabolic rate, reduced core body temperature, and prolonged fasting—may collectively contribute to the enhanced longevity observed in some hibernators. While this effect is intriguing, it is observed only in a subset of hibernators, indicating that

other factors likely play significant roles in the aging processes of different species. Understanding these mechanisms offers valuable insights into how environmental factors and metabolic adaptations influence aging and lifespan across various species.

## 3. Health risks associated with long-term cold exposure

### 3.1. Non-optimal temperatures and mortality among the elderly population

Recent studies have extensively examined the impact of non-optimal temperatures on mortality, consistently highlighting that several million deaths occur annually, with the majority affecting elderly populations. A comprehensive analysis of data from 1980 to 2016 across nine countries—Brazil, Chile, China, Colombia, Guatemala, Mexico, New Zealand, South Africa, and the USA—revealed that prolonged exposure to cold temperatures generally results in more deaths than exposure to heat. Additionally, both acute heat and cold exposure can increase or decrease the mortality risk for various causes of death [24]. Another extensive study spanning from 2000 to 2019, including 854 cities across 30 European countries, emphasized the severe impact of cold-related mortality, with an estimated 130,228 deaths annually due to extreme cold compared to 13,589 deaths due to heat. Cold-related mortality was notably higher in Eastern Europe and predominantly affected older populations [16]. Despite an anticipated overall decrease in cold-related mortality due to global warming, the aging population, projected to increase from 9 % to 16 % by 2050, is expected to counteract this trend. As a result, cold-related mortality may rise by 0.1 % to 0.4 % under various levels of global warming, indicating that older adults will remain vulnerable to cold temperatures. This underscores that cold exposure continues to impose a substantial health burden, remaining a critical public health concern despite the warming climate [25]. This heightened risk among older adults is attributed to factors such as a reduced thermoregulatory capacity, a higher prevalence of chronic health conditions, and an increased social isolation [16,24,25].

### 3.2. Impaired thermoregulation and increased disease risk in older adults

As individuals age, their ability to regulate body temperature declines due to several physiological changes. This impaired thermoregulatory capacity makes older adults more vulnerable to extreme temperatures. In cold climates, they face a higher likelihood of circulatory diseases such as myocardial infarction and stroke [17,26]. Extreme cold significantly increases the mortality risk from circulatory diseases in older adults [26]. Cold days and cold waves have a pronounced effect on the elderly, with the greatest impact occurring on days following extreme cold weather. Women and individuals aged 85 years old and above are particularly vulnerable, with a higher relative risk of death from circulatory diseases compared to younger individuals [26]. Several physiological changes contribute to the impaired thermoregulation in older adults.

Older adults have relatively reduced heat production and impaired thermal perception, making it harder for them to generate heat and detect temperature changes, which compromises their ability to maintain homeostasis in cold environments. Aging leads to a decline in the number and efficiency of sweat glands, decreasing the body's capacity to cool itself through sweating [27]. This is accompanied by a reduction in sweat rate and cutaneous vasodilation, both of which are essential for heat dissipation [27]. This reduction is due to both a decrease in the number of active sweat glands and impaired secretion per gland. Additionally, reduced functionality of cutaneous vasodilation further impairs temperature regulation. A slower metabolic rate in older adults also lowers internal heat production, increasing their vulnerability in cold environments.

Older adults tend to have reduced sensitivity to cold, altered autonomic nervous activity, impaired vasomotor control, and diminished
muscle mass, which reduces their ability to generate heat through shivering [28]. As thermal perception declines with age, they become less sensitive to both heat and cold exposure. The reaction time to thermal stimuli is also impaired in aged skin, further contributing to the challenges in thermoregulation. Many older adults have chronic diseases such as diabetes, cardiovascular diseases, and respiratory issues that impair thermoregulation [29]. Moreover, medications commonly prescribed to older adults, such as diuretics and beta-blockers, can interfere with the body's natural cooling processes [30].

# 4. Potential anti-aging benefits of cold exposure

Cold exposure, particularly through controlled methods such as cryotherapy, cold water immersion, and cold plunges, has shown promise in affecting key parameters related to aging. Cryotherapy, one of the most commonly used cooling techniques, involves exposing individuals to extremely cold air (−50 °C to −195 °C) for 2 to 5 min. This technique can be administered through whole-body cryotherapy (WBCT) in a controlled chamber or Partial Body Cryotherapy in a cryocabine that excludes the head. It is widely used for therapeutic purposes [31] and to enhance athletic performance [32].

## 4.1. Reduction of inflammation

Cold exposure, particularly through controlled methods such as cold-water immersion or WBCT, among others, has been shown to significantly reduce inflammation by modulating cytokine production. Acute cold exposure stimulates the release of anti-inflammatory cytokines like IL-10 while reducing pro-inflammatory cytokines such as IL-2, IL-6, and IL-8 [33,34]. This shift in cytokine balance helps to regulate inflammatory responses, making cold exposure especially beneficial in managing chronic low-grade inflammation, which is commonly associated with aging and various age-related diseases. At the molecular level, cold exposure may inhibit the nuclear factor kappa B (NF-κB) signaling pathway, which is essential to the production of pro-inflammatory cytokines [35]. By suppressing NF-κB activation, cold exposure reduces the expression of genes involved in chronic inflammation [35]. Additionally, it promotes the phosphorylation and activation of AMP-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis that indirectly inhibits inflammation [36]. Furthermore, animal [37] and human [38] metabolomic studies showed that the exposure to low-temperature attenuates markers of injury and inflammation by decreasing pro-inflammatory metabolites (lactate, succinate, β-alanine, methionine, fumarate, and acetate) and increasing anti-inflammatory and antioxidant markers.

WBCT has demonstrated significant effects in reducing pro-inflammatory cytokines in healthy individuals and those with pathological conditions such as obesity. Aging and obesity are linked to a decline in muscle mass and an increase in body fat, which elevates inflammatory cytokine levels and accelerates biological aging. Obesity is associated with chronic low-grade inflammation [39], marked by elevated levels of pro-inflammatory cytokines that contribute to various metabolic disorders [40], including insulin resistance [41], type 2 diabetes [41], and cardiovascular diseases [42]. Obese individuals often exhibit higher levels of inflammatory markers like IL-6, TNF-α, and resistin [39]. WBCT has been shown to reduce these pro-inflammatory cytokines, suggesting its potential effectiveness in lowering systemic inflammation and improving metabolic health [43,44]. In this context, cold exposure reduces macrophage infiltration in white adipose tissue, a key driver of inflammation. It also shifts macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, thereby attenuating adipose tissue inflammation [45]. This mechanism is pivotal in breaking the cycle of inflammation and metabolic dysfunction commonly observed in obesity and aging.

In healthy individuals, WBCT also showed significant anti-inflammatory effects. Studies reported that WBCT significantly

increased anti-inflammatory cytokines like IL-10 and reduced pro-inflammatory cytokines such as IL-1α, with the most pronounced effects observed in participants undergoing prolonged treatment sessions [12,46]. These findings highlight the potential of WBCT as a therapeutic intervention for managing chronic inflammation and promoting overall health.

Further studies have demonstrated that cryotherapy can decrease levels of inflammatory markers such as C-reactive protein (CRP) and interleukin 1 beta (IL-1β), this shift helps mitigate systemic inflammation and pain in patients suffering from rheumatoid arthritis and other autoimmune disorders. WBCT stimulates the immune response by increasing the activity of natural killer cells, lymphocytes, and other immune cells involved in the body's defense mechanisms. Moreover, cryotherapy significantly decreases inflammatory markers such as TNF-α, NF-κB, TGF-β, and MMP-9, underscoring its potent anti-inflammatory effects. By reducing macrophage infiltration and the accumulation of inflammatory cytokines, cryotherapy effectively manages chronic inflammation, a major driver of aging and age-related diseases [34].

Notably, cryotherapy reduces inflammation without impairing muscle regeneration or extracellular matrix remodeling. This balance is crucial for preserving tissue health and function, suggesting that cryotherapy may support the body's natural repair processes while mitigating inflammation [34]. The ability of cryotherapy to minimize secondary muscle damage and regulate cellular metabolism underscores its potential benefits for metabolic health [34]. Efficient metabolic regulation is essential for longevity, and cryotherapy's impact on key metabolic enzymes supports this role (Table 1).

## 4.2. Oxidative stress reduction

Cold exposure, particularly through WBCT and other controlled methods, has shown significant potential in reducing oxidative stress, a major factor in the aging process. Oxidative stress occurs when there is an imbalance between the production of ROS and the body's antioxidant defenses, leading to cellular damage and contributing to aging, and various age-related diseases. Acute cold exposure has been shown to reduce the production of ROS by stabilizing mitochondrial function [11,12]. This effect is particularly important in pathological conditions, where ROS levels are often elevated, contributing to tissue damage and inflammation.

WBCT exposes the body to extremely cold temperatures, which enhances the activity of antioxidant enzymes and reduces ROS production [47]. Indeed, mitochondrial stabilization during cold exposure may be mediated by enhanced coupling efficiency of the electron transport chain, that reduces electron leakage and subsequent ROS generation [48]. Additionally, the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway may play a pivotal role in cellular defense mechanisms, as Nrf2 upregulates the transcription of antioxidant genes, thereby increasing the cellular capacity to neutralize ROS [49]. By mitigating oxidative stress, cold exposure may help protect against cellular deterioration and may prevent the accumulation of senescence-inducing stressors.

Although direct studies on the effects of cold exposure on cellular senescence are scarce, evidence suggest that cold exposure modulates key processes associated with senescence, such as oxidative stress and chronic inflammation [11]. As previously mentioned, cold exposure activates antioxidant pathways like Nrf2, mitigating oxidative damage caused by excessive ROS. Furthermore, cold exposure reduces pro-inflammatory cytokines while promoting anti-inflammatory responses, which can alleviate the systemic burden associated with the senescence-associated secretory phenotype [50]. These mechanisms may indirectly influence the accumulation and effects of senescent cells, potentially slowing the aging process. However, further research is needed to establish direct connections between cold exposure and cellular senescence. Additionally, the impact of cold exposure depends on its intensity and duration, with controlled exposure offering benefits, while
<table><caption>**Table 1**
Summary of cold exposure's potential anti-aging benefits, aspect, and evidence.</caption><thead><tr><th>Aspect</th><th>Evidence</th><th>Reference</th></tr></thead><tbody><tr><td>Reduction of Inflammation</td><td>- Short and controlled cold exposure (e.g., cryotherapy, cold water immersion) reduces inflammation by modulating cytokine production.<br/>- Decreases pro-inflammatory cytokines (IL-2, IL-6, IL-8) and increases anti-inflammatory cytokines (IL-10).<br/>- Demonstrates significant effects in reducing inflammation in both healthy individuals and those with obesity, rheumatoid arthritis, and other conditions.<br/>- Reduces CRP, IL-1β, TNF-α, NF-κB, TGF-β, and MMP-9 levels.<br/>- WBCT stimulates the immune response by increasing the activity of natural killer cells, lymphocytes, and other immune cells involved in the body's defense mechanisms.</td><td>[12,33,34,37,38,43,44,46]</td></tr><tr><td>Oxidative Stress Reduction</td><td>- Cold exposure through WBCT enhances antioxidant enzyme activity and reduces ROS production, protecting cells from oxidative damage.<br/>- Shows antioxidant effects in patients with MS by improving plasma antioxidative status and increasing SOD and uric acid levels.<br/>- Regular cold exposure, such as winter swimming, increases enzymatic protection and activates the body's natural antioxidant defenses.<br/>- Supports muscle regeneration and overall metabolic health by reducing oxidative stress.</td><td>[11,12,47,51,52]</td></tr><tr><td>Improved Metabolic Regulation</td><td>- Cold exposure activates BAT, increasing energy expenditure and improving metabolic efficiency.<br/>- Enhances thermogenic capacity, insulin sensitivity, and glucose metabolism, counteracting age-related metabolic decline.<br/>- Regular cold exposure promotes the conversion of white fat to brown fat, offering metabolic benefits that support healthier aging and longevity.<br/>- Aging reduces BAT activity, but cold exposure may mitigate this decline, improving lipid metabolism and reducing fat accumulation.</td><td>[53-55,58-60,64-66]</td></tr><tr><td>Improved Cardiovascular Health</td><td>- Cold exposure induces vasoconstriction, increasing venous return and cardiac output to maintain core body temperature and support circulatory function.<br/>- Increases myocardial oxygen demand, leading to coronary vasodilation and improved coronary blood flow.<br/>- Activates the PNS, lowering heart rate and improving HRV.<br/>- Regular cold exposure can</td><td>[70-72,74,75,77,78]</td></tr></tbody></table>

<table><caption>**Table 1 (continued)**</caption><thead><tr><th>Aspect</th><th>Evidence</th><th>Reference</th></tr></thead><tbody><tr><td></td><td>enhance vagal tone and cardiovascular fitness in healthy individuals, though caution is advised for those with pre-existing cardiovascular conditions.<br/>- Studies show a connection between cardiovascular health and increased lifespan, assessed using the Life's Essential 8 metrics.</td><td></td></tr></tbody></table>

BAT: Brown Adipose Tissue, CRP: C-reactive protein, IL: Interleukin, MS: Multiple Sclerosis, MMP: Matrix Metalloproteinase, PNS: Parasympathetic Nervous System, SOD: Superoxide Dismutase, TNF: Tumor Necrosis Factor, TGF: Transforming Growth Factor, HRV: Heart Rate Variability, WBCT: Whole Body Cryotherapy.

prolonged exposure may exacerbate cellular stress.

Recent clinical investigations have demonstrated that WBCT has antioxidant effects in patients with multiple sclerosis (MS), improving plasma total antioxidative status, superoxide dismutase (SOD), and uric acid levels. While the exact molecular mechanisms behind cryotherapy's ability to minimize oxidative damage are not fully understood, it is proposed that long-term WBCT enhances the activity of antioxidative enzymes. Repeated exposure to acute cold temperatures over several months may trigger adaptive responses that enhance the body's resistance to oxidative stress [51].

Furthermore, in pathological contexts, WBCT was shown to be efficient in reducing oxidative stress by enhancing the activity of antioxidative enzyme activity or partially inhibiting the generation of ROS in MS [51].

Additionally, regular cold exposure, such as cryotherapy or cold water immersion, has been shown to increase antioxidant levels in the body. This adaptation to cold stimuli, often referred to as body hardening, is believed to strengthen the antioxidant defense system. Research by Siems et al. [52] demonstrated that regular winter swimming or intense endurance exercise increases enzymatic protection, suggesting an activation of the body's natural antioxidant defenses. Notably, winter swimmers exhibit elevated baseline levels of reduced glutathione, a critical intracellular antioxidant that mitigates oxidative damage by neutralizing free radicals [52].

Cryotherapy reduces oxidative stress while enhancing muscle regeneration and supporting metabolic health. By minimizing secondary muscle damage and optimizing cellular metabolism, cryotherapy underscores its potential to enhance overall metabolic regulation, which is essential for longevity. Its ability to influence key metabolic enzymes further supports its role in reducing oxidative stress and fostering healthy aging (Table 1).

### 4.3. Improved metabolic regulation

Metabolic health plays a crucial role in the aging process, affecting both lifespan and healthspan. As individuals age, metabolic processes often become less efficient, leading to increased central adiposity, sarcopenia, and insulin resistance. These changes are exacerbated by a sedentary lifestyle and poor dietary habits, contributing to the development of chronic diseases such as type 2 diabetes, cardiovascular diseases, and obesity. Maintaining good metabolic health through regular physical activity, balanced nutrition, and metabolic interventions can mitigate these age-related changes, promoting healthier aging and potentially extending lifespan. Effective metabolic regulation supports cellular repair mechanisms, reduces oxidative stress, and enhances overall physiological function, all of which are essential for longevity.

Cold exposure, a promising non-pharmacological intervention, can significantly impact the regulation of metabolic health, which is often
altered in the aging population [53]. One of the key mechanisms is through the activation of BAT. BAT is specialized in heat production through non-shivering thermogenesis, mediated by uncoupling protein 1 (UCP1) in its abundant mitochondria [54,55]. This process increases energy expenditure and improves metabolic efficiency [55]. It is driven by the sympathetic nervous system (SNS), which releases norepinephrine in response to cold exposure. Norepinephrine binds to β3-adrenergic receptors on brown adipocytes, triggering a signaling cascade that increases intracellular cyclic AMP (cAMP) levels and activates protein kinase A (PKA) [56]. The cAMP-PKA pathway leads to phosphorylation of transcription factors, which is crucial for UCP1 gene expression [57].

Cold exposure stimulates the conversion of white fat to brown fat, enhancing thermogenic capacity and metabolic activity [58,59]. This can improve insulin sensitivity and glucose metabolism, counteracting some of the metabolic declines associated with aging [60]. The 'browning' process, is facilitated by cold-induced release of irisin and fibroblast growth factor 21 (FGF21) [61]. Irisin, a myokine secreted during cold exposure, promotes the expression of UCP1 in white adipocytes, while FGF21 enhances thermogenic gene expression in both white and brown adipose tissue [62,63]. Both irisin and FGF21 contribute to improved metabolic flexibility and energy expenditure [61,62]. Some studies suggest that WBCT may improve insulin sensitivity, which is crucial for maintaining glucose homeostasis [64,65]. Enhanced insulin sensitivity helps the body regulate blood sugar levels more effectively and can be beneficial in managing or preventing type 2 diabetes. WBCT may induce long-term adaptive responses that enhance metabolic regulation [66]. These adaptations could include improved mitochondrial function, better regulation of glucose and lipid metabolism, and increased resilience to metabolic stressors.

However, aging is associated with a decline in BAT activity and mass, reducing its beneficial effects on metabolism [67]. This decline in BAT may contribute to the onset of metabolic disorders such as diabetes and obesity [55,68]. Factors such as reduced expression of UCP1, impaired mitochondrial function, and decreased responsiveness of the sympathetic nervous system contribute to this decline [67]. Enhancing BAT function could counteract age-related metabolic decline and support healthier aging by maintaining a higher metabolic rate, improving lipid metabolism, and reducing fat accumulation [68]. Regular and controlled cold exposure can activate BAT, offering metabolic benefits that enhance metabolic health and potentially promote longevity in older adults [53,58,69] (Table 1).

While these findings highlight the potential benefits of controlled and short-term cold exposure, it is important to consider the broader context of cold exposure in everyday life. Controlled settings provide therapeutic use of cold exposure, ensuring benefits such as reduced inflammation and improved metabolic health. In contrast, permanent or chronic exposure to cold environments, as experienced by populations living in colder climates, presents a different set of challenges and risks. Epidemiological evidence reveals higher mortality and disease rates among individuals living in cold environments, highlighting the complexities and potential contradictions in the effects of cold exposure on health and aging

## 4.4. Cardiovascular health

Cardiovascular health plays a crucial role in determining both healthspan and lifespan, extending beyond fitness. Studies have consistently shown that individuals with optimal cardiovascular health, assessed using the American Heart Association's Life's Essential 8 metrics, tend to live longer and spend more years free from chronic diseases [70,71]. Furthermore, individuals with higher Life's Essential 8 scores were found to have an increased life expectancy of 8.1 years at age 50 compared to those with lower scores [70,71].

Cold exposure has complex effects on cardiovascular health. While some evidence suggests potential benefits in controlled settings [72], data from large-scale clinical studies are currently limited. A systematic

review and meta-analysis by Fan et al. [17] analyzed 159 studies found that each 1 °C decrease in temperature increased cardiovascular disease-related mortality by 1.6% and morbidity by 1.2%. The study highlighted that cold exposure could be a critical risk factor for cardiovascular diseases, with varying effects across different disease types and climate zones. The adverse cardiovascular effects of cold exposure are driven by several key mechanisms. Sympathetic nervous system excitation leads to the release of catecholamines, causing vasoconstriction, increased heart rate, and elevated blood pressure, thereby increasing the workload on the heart. Additionally, renin-angiotensin system activation occurs as cold-induced vasoconstriction reduces renal perfusion, prompting the release of renin and a subsequent increase in angiotensin II, further exacerbating hypertension [73]. Lastly, the accumulation of harmful metabolites, such as ROS from reduced oxygen delivery, can impair endothelial function, promote inflammation, and contribute to long-term vascular damage. These interconnected mechanisms underscore the potential cardiovascular risks associated with cold exposure, particularly in vulnerable populations [72,73].

In healthy individuals, cold-induced vasoconstriction can increase venous return and cardiac output, helping to maintain core body temperature and circulatory function. This response is generally well-regulated and may stimulate beneficial cardiovascular adaptations, such as improved vascular function and coronary regulation [74,75]. Despite these potential benefits, much of the existing evidence derives from smaller studies or preclinical research, leaving the long-term effects of cold exposure on cardiovascular health in humans uncertain. The study of Jdidi et al. [76] examined the effects of cryostimulation and cold-water immersion on cardiovascular and cardiac autonomic control responses in healthy individuals. While the study provided valuable insights into acute responses, it did not demonstrate conclusive evidence of long-term cardiac benefits, further emphasizing the need for robust clinical research.

One proposed benefit of cold exposure is its ability to increase myocardial oxygen demand, leading to autoregulatory increases in coronary blood flow, particularly in healthy coronary arteries. Additionally, facial cooling or whole-body cold exposure has been shown to stimulate the parasympathetic nervous system, potentially lowering heart rate and improving vagal tone, as evidenced by enhanced heart rate variability, a key marker of cardiac autonomic health [77,78]. These findings align with preclinical studies, such as the work by Mohan et al. [79], which suggested mechanisms involving sirtuin activation in cardiac mitochondrial function. However, these findings are derived from animal models, limiting their direct applicability to human cardiac health.

While cold exposure may support cardiovascular fitness and resilience in controlled settings, the lack of large-scale clinical studies warrants caution in extrapolating these effects to broader populations [72]. Current evidence predominantly indicates that cold exposure poses risks to cardiovascular health, and potential benefits remain speculative. It is also essential to note the significant risks of cold exposure in individuals with pre-existing cardiovascular conditions, such as coronary artery disease. In these cases, cold exposure can impair coronary perfusion, increasing the risks of ischemia and angina [80]. Controlled settings, such as cryostimulation or cold-water immersion, may mitigate some risks, but further research is needed to determine whether these benefits translate to significant improvements in healthspan or lifespan.

Given this strong connection between cardiovascular health and longevity, the potential positive impact of cold exposure on heart function suggests it may help extend lifespan. By improving cardiovascular fitness and supporting heart health, cold exposure could serve as a complementary strategy for promoting both improved health and increased longevity.
## 5. Cold exposure as a complementary hormetic intervention for longevity

Interventions that induce a state of perceived adversity, such as high-intensity exercise, intermittent fasting, and intermittent hypoxia, have garnered significant attention for their ability to enhance lifespan and healthspan. These effects are grounded in the principle of hormesis, which describes the biological phenomenon where exposure to mild stressors triggers adaptive responses that strengthen cellular resilience and improve overall physiological function [81,82]. High-intensity interval exercise, for instance, induces transient oxidative stress and inflammation, promoting the activation of antioxidant pathways and mitochondrial biogenesis through mechanisms such as AMPK and PGC-1α signaling [83,84]. Similarly, intermittent fasting (IF) induces autophagy, upregulates sirtuin activity, and reduces insulin-like growth factor 1 (IGF-1) levels, mechanisms strongly linked to extended lifespan and a decreased risk of age-related diseases [85,86]. By enhancing metabolic flexibility and reducing chronic inflammation, IF further promotes cellular homeostasis and longevity [87]. Intermittent hypoxia (IH), studied in the context of altitude exposure or controlled protocols, has been shown to stimulate erythropoiesis, angiogenesis, and the production of neuroprotective factors, while enhancing mitochondrial efficiency [88,89].

Although direct studies on the effects of cold exposure on longevity biomarkers remain limited, their physiological mechanisms suggest parallels with these interventions. Cold exposure reduces chronic inflammation through the modulation of pro- and anti-inflammatory cytokines, enhances metabolic health via the activation of BAT and increased insulin sensitivity, and mitigates oxidative stress by stimulating antioxidant defenses. These effects are likely mediated by pathways such as PGC-1α, Nrf2, and AMPK, which are also central to the hormetic responses observed with exercise, fasting, and hypoxia.

Importantly, cold exposure may not only replicate some of these benefits but also exert additive or synergistic effects when combined with other hormetic interventions. For instance, pairing cold exposure with IF could amplify metabolic flexibility by promoting lipid oxidation and improving glucose homeostasis, while combining it with high-intensity exercise may further enhance recovery and stress adaptation through improved circulation and reduced muscle inflammation [90]. Similarly, incorporating cold exposure with IH could potentiate mitochondrial adaptations and antioxidant responses, creating a multifaceted approach to maximizing healthspan and lifespan.

To fully elucidate the potential of cold exposure as an anti-aging intervention, future research should prioritize studies that directly measure longevity biomarkers, such as telomere length, senescence markers, and cellular stress responses, both as a standalone strategy and in combination with other proven interventions. This integrated approach holds promise for developing comprehensive protocols to enhance resilience and promote healthy aging.

## 6. Conclusion

Controlled short-term cold exposure allows promising anti-aging benefits, including reduced inflammation, lower oxidative stress, improved metabolic regulation, and cardiovascular health. These findings highlight the therapeutic potential of cold exposure in controlled settings. However, it is crucial to consider the broader implications of cold exposure in everyday life, particularly in contexts of permanent or chronic exposure experienced by populations living in colder climates.

Epidemiological evidence shows higher mortality and disease rates among people in such environments, revealing the complexities and potential contradictions in the effects of cold exposure on health and aging. The risks associated with long-term cold exposure, particularly for older adults, are significant and include increased rates of mortality and morbidity.

While short-term controlled cold exposure shows clear benefits,

there is a notable gap in comprehensive cohort and longitudinal studies investigating the long-term effects of permanent cold exposure on aging biomarkers and physiological aging processes. Therefore, more research is needed to determine if the anti-aging benefits of cold exposure observed in controlled settings translate to real-world scenarios of chronic cold exposure. Future studies should aim to provide a more nuanced understanding of how cold exposure impacts the aging process and inform guidelines for leveraging its benefits while mitigating its risks.

### Permission statement

Not applicable.

### CRediT authorship contribution statement

**Ayoub Boulares:** Writing – review & editing, Writing – original draft, Supervision, Conceptualization. **Hela Jdidi:** Writing – review & editing, Writing – original draft. **Wafa Douzi:** Writing – review & editing, Writing – original draft, Conceptualization.

### Funding

This work received no external funding.

### Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

### Acknowledgments

Not applicable.

### Data availability

The data employed in this review are secondary and can be accessed through the articles cited throughout the review.

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