How Metabolic Syndrome Makes Aging Worse

Metabolic syndrome drives many of the hallmarks of aging, and multiple hallmarks of aging drive metabolic syndrome in a vicious, accelerating cycle.

Central obesity, high triglycerides, low HDL cholesterol, high blood pressure, and elevated fasting glucose comprise a cluster of metabolic disorders that increase the risk of cardiovascular disease and type 2 diabetes and define metabolic syndrome [1].

All of the factors of metabolic syndrome are associated not just with age but with accelerated aging.  For example, age-associated inflammation can lead to insulin resistance, impaired glucose metabolism, and dyslipidemia, all of which are components of metabolic syndrome [2].

A healthy lifestyle can reverse or significantly slow the progress of metabolic syndrome in many instances [3, 4]. There are multiple mechanisms linking metabolic syndrome and the primary hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, altered proteostasis, and disabled macroautophagy [5].

Genomic instability

Metabolic syndrome is linked to an increased risk of genomic instability and thus DNA damage. This, in turn, increases the risk of cancer and other diseases [6, 7].

Factors associated with metabolic syndrome, including insulin resistance, oxidative stress, and chronic inflammation, drive genomic instability. Insulin resistance, for example, can cause increased production of insulin and insulin-like growth factors, which can promote the growth and proliferation of cells and increase the risk of DNA damage [8].

Oxidative stress, which occurs when there is an imbalance between the production of reactive oxygen species (ROS) and the body’s antioxidant defenses, can also contribute to genomic instability. ROS can damage DNA and other cellular components, leading to mutations and other forms of genomic instability [7].

Chronic inflammation, which is a hallmark of metabolic syndrome, can also contribute to genomic instability through the release of cytokines and other molecules that can damage DNA and increase the risk of mutation [9]. Furthermore, oxidative damage is also a product of inflammation [10].

Telomere attrition

Telomeres are the protective caps at the end of chromosomes. They play a critical role in maintaining genomic stability. Telomere attrition, which refers to the gradual shortening of telomeres over time, is a hallmark of aging [11].

Metabolic syndrome has been linked to accelerated telomere attrition through increased oxidative stress, inflammation, and insulin resistance. Oxidative stress can damage telomeric DNA, leading to telomere shortening [12], while inflammation can accelerate telomere attrition by promoting cellular aging and DNA damage. Insulin resistance, which is a hallmark of metabolic syndrome, has also been linked to telomere attrition, likely due to the role of insulin in promoting cell proliferation and DNA replication [13-15].

Epigenetic alterations

Epigenetic alterations are changes in the way that genes are expressed without changing the underlying DNA sequence. These alterations can occur in response to environmental factors such as diet, physical activity, and exposure to toxins. Several studies have suggested that epigenetic alterations play a role in metabolic syndrome and that metabolic syndrome in a vicious cycle drives further alterations in the epigenome.

Additionally, epigenetic changes have been associated with obesity, a key component of metabolic syndrome. Adipose tissue, which is the main place that the body stores fat, has been shown to undergo significant epigenetic changes in response to changes in nutrient availability and metabolic stress. These changes can contribute to insulin resistance and other metabolic abnormalities [16, 17]. For example, high-fat diets have been shown to induce changes in DNA methylation patterns that lead to altered gene expression in a way that favors metabolic syndrome [18].

Loss of proteostasis

Proteostasis refers to the maintenance of protein homeostasis, which is essential for cellular and organismal health. The loss of proteostasis, which can occur due to genetic and environmental factors, is associated with several age-related diseases, including metabolic syndrome [19].

Several mechanisms have been proposed to explain the relationship between the loss of proteostasis and metabolic syndrome. For example, the accumulation of misfolded or aggregated proteins can activate stress response pathways, such as the unfolded protein response (UPR), which can lead to insulin resistance and other metabolic abnormalities [20].

Furthermore, proteostasis is closely linked to mitochondrial function, which is essential for cellular energy metabolism. Mitochondrial dysfunction, which can result from impaired proteostasis, can contribute to metabolic abnormalities by reducing cellular energy production and increasing oxidative stress [21].

Finally, the loss of proteostasis can also contribute to chronic inflammation, which is a hallmark of metabolic syndrome. Misfolded or damaged proteins can activate the immune system and induce the release of inflammatory cytokines, which can contribute to insulin resistance and other metabolic abnormalities [22]. Conversely, metabolic syndrome can aggravate faltering proteostasis through several mechanisms.

Metabolic syndrome often leads to increased oxidative stress, which can damage proteins and make them misfold. This misfolding disrupts proteostasis and can lead to the formation of protein aggregates, which are harmful to cells [23].

Chronic inflammation, a common symptom of metabolic syndrome, can also disrupt proteostasis. Inflammation can lead to the production of cytokines that interfere with the normal functioning of the proteostasis network. For example, inflammation can affect the function of the endoplasmic reticulum, a cellular organelle involved in protein folding [24].

Insulin resistance can also disrupt proteostasis. Insulin signaling is crucial for many aspects of cellular function, including protein synthesis. Therefore, insulin resistance can lead to the overproduction or underproduction of certain proteins, disrupting the balance of the proteostasis network [25].

High levels of lipids, a common characteristic of metabolic syndrome, can cause lipotoxicity, leading to the impairment of various cellular processes, including proteostasis. High lipid levels can induce endoplasmic reticulum stress and initiate the unfolded protein response pathway, which can ultimately disrupt the balance of protein synthesis, folding, and degradation [26].

Lastly, prolonged high blood sugar levels can lead to the formation of advanced glycation end-products (AGEs). These AGEs can alter protein structure and function, thus contributing to impaired proteostasis [27].

Disabled autophagy

Autophagy is a process by which cells break down and recycle damaged or dysfunctional cellular components. Autophagy is essential for maintaining cellular homeostasis and is involved in a wide range of physiological processes, including nutrient metabolism, inflammation, and cellular stress response [28].

Disabled autophagy has been implicated in the development of metabolic syndrome. Several studies have shown that impaired autophagy is associated with insulin resistance, dyslipidemia, and other metabolic abnormalities [28, 29].

One potential mechanism by which impaired autophagy contributes to metabolic syndrome is through the accumulation of damaged organelles, such as mitochondria, which can lead to increased oxidative stress and inflammation [30].

Furthermore, autophagy plays a crucial role in the regulation of lipid metabolism. Impaired autophagy has been shown to result in the accumulation of lipids in cells and tissues, which can lead to dyslipidemia and non-alcoholic fatty liver disease (NAFLD), a common complication of metabolic syndrome [29].

Finally, autophagy is involved in the regulation of energy metabolism and glucose homeostasis. Impaired autophagy can lead to the accumulation of misfolded proteins and other cellular components, which can activate stress response pathways, such as the UPR, and lead to insulin resistance and impaired glucose metabolism [22].

Antagonistic and integrative hallmarks of aging

The integrative and antagonistic hallmarks of aging, which are interconnected and influence each other, are also affected by metabolic syndrome. They collectively contribute to the aging phenotype and age-related diseases. They include deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation and dysbiosis [31].

Deregulated nutrient sensing

Nutrient sensing is the ability of cells to sense and respond to changes in nutrient availability. This process plays a crucial role in the regulation of energy metabolism and is essential for maintaining metabolic homeostasis. Deregulated nutrient sensing, which can occur due to genetic and environmental factors, may lead to metabolic syndrome [32].

One way in which deregulated nutrient sensing can contribute to metabolic syndrome is through insulin resistance [33]. Insulin is a hormone that regulates glucose and lipid metabolism. Deregulated nutrient sensing can disrupt insulin signaling pathways, leading to impaired glucose and lipid metabolism along with insulin resistance [34].

Furthermore, deregulated nutrient sensing can lead to the accumulation of excess nutrients, such as glucose and fatty acids, in cells and tissues [35]. This can promote lipotoxicity, a condition in which excess lipids accumulate in tissues and lead to cellular dysfunction and inflammation. Lipotoxicity can contribute to insulin resistance and other metabolic abnormalities [36, 37].

Additionally, deregulated nutrient sensing can lead to chronic low-grade inflammation (inflammaging) [38], which is a hallmark of metabolic syndrome. Excess nutrient availability can activate immune cells and promote cytokine release [39].

Finally, deregulated nutrient sensing can contribute to NAFLD. Excess nutrient availability can lead to the accumulation of lipids in liver cells, leading to hepatic steatosis and NAFLD [40].

Mitochondrial dysfunction

Mitochondria are organelles within cells that play a critical role in energy production and metabolism. Mitochondrial dysfunction, which refers to impaired mitochondrial function, has been implicated in metabolic syndrome [41].

Mitochondrial dysfunction can contribute to metabolic syndrome through several mechanisms. For example, impaired mitochondrial function can lead to reduced energy production, which can impair glucose and lipid metabolism and contribute to insulin resistance and other metabolic abnormalities [42]. Mitochondrial dysfunction can also lead to the accumulation of ROS, can contribute to NAFLD [43], and can contribute to inflammation through immune cell and cytokine activation [44].

Cellular senescence

Cellular senescence is a process in which cells stop dividing and enter a state of irreversible growth arrest. Cellular senescence plays a crucial role in aging and is associated with several age-related diseases, including metabolic syndrome [45]. The inflammaging associated with metabolic syndrome also increases the risk of cellular senescence [46].

Furthermore, metabolic syndrome is associated with oxidative stress, which can contribute to cellular senescence by inducing DNA damage and other forms of cellular stress. Oxidative stress can activate stress response pathways, such as the p53 pathway, which can induce cellular senescence [47]. Telomere attrition can also contribute to cellular senescence by activating stress response pathways and inducing cellular damage [48].

Finally, metabolic syndrome is associated with impaired proteostasis, which can contribute to cellular senescence by inducing the accumulation of misfolded or damaged proteins, leading to the activation of stress response pathways and other forms of cellular stress [49].

Stem cell exhaustion

Stem cell exhaustion refers to the depletion of the pool of stem cells in tissues due to aging or other factors. Stem cells play a crucial role in tissue regeneration and repair, and their exhaustion has been implicated in the development of several age-related diseases, including metabolic syndrome [41].

Metabolic syndrome is associated with the accumulation of cellular damage and stress, which can contribute to the depletion of stem cells. Inflammaging, oxidative stress, and impaired proteostasis can all induce cellular damage and stress and contribute to stem cell exhaustion [50].

Furthermore, metabolic syndrome is associated with impaired tissue regeneration and repair, which can be attributed, at least in part, to the depletion of stem cells. Impaired tissue regeneration and repair can lead to the accumulation of damage and stress, contributing to metabolic abnormalities [50, 51].

In addition, metabolic syndrome has been associated with impaired angiogenesis, which is the process by which new blood vessels form from pre-existing ones. Angiogenesis is essential for tissue regeneration and repair, and its impairment can  alsocontribute to metabolic abnormalities [52].

Finally, metabolic syndrome is associated with insulin resistance, which can impair the function of stem cells through reactive oxygen species production, activation of inflammatory pathways, and disruption of the insulin/IGF signaling pathway. Insulin resistance can contribute to the depletion of stem cells and impair tissue regeneration and repair [34, 53, 54].

Altered intercellular communication and metabolic syndrome

Intercellular communication refers to the exchange of information between cells, which is essential for maintaining cellular homeostasis and physiological function. Alterations in intercellular communication have been implicated in the development of metabolic syndrome [41], and the inflammaging associated with metabolic syndrome can lead to intercellular communication disruption [55, 56].

Furthermore, altered intercellular communication can impair the function of adipose tissue, which plays a crucial role in energy metabolism and is dysregulated in metabolic syndrome. Adipose tissue communicates with other tissues through the release of adipokines, which can influence glucose and lipid metabolism [57]. Alterations in adipokine secretion can contribute to insulin resistance and other metabolic abnormalities [58].

In addition, altered intercellular communication can impair the function of the gut microbiota, which plays a critical role in nutrient metabolism and the regulation of inflammation. The gut microbiota communicates with host cells through the release of metabolites and other molecules, which can influence energy metabolism and immune function. Alterations in the gut microbiota can contribute to insulin resistance and other metabolic abnormalities [59]. Finally, altered intercellular communication can contribute to NAFLD as well [60, 61].

Inflammaging

Inflammaging, which is a common link between metabolic syndrome and other hallmarks of aging, is associated with insulin resistance, dyslipidemia, and hypertension [62]. Several factors can contribute to this, including excessive nutrients leading to immune activation [63]. Metabolic stress, such as that caused by insulin resistance, can also activate immune cells and promote inflammation [64].

Another factor that can contribute to chronic inflammation in metabolic syndrome is the accumulation of visceral adipose tissue. Adipose tissue produces pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), which can contribute to  insulin resistance and other metabolic abnormalities [65].

Furthermore, chronic inflammation can lead to the activation of stress response pathways, such as the UPR [66]. Chronic inflammation can also contribute to NAFLD [60].

Dysbiosis

Dysbiosis refers to an imbalance in the gut microbiota, the complex community of microorganisms that inhabit the gastrointestinal tract. Dysbiosis has been implicated in the development of several diseases, including metabolic syndrome [67].

The gut microbiota plays a critical role in nutrient metabolism and the regulation of inflammation. Dysbiosis can impair the function of the gut microbiota and contribute to metabolic abnormalities [67].

One of these pathways is insulin resistance [68, 69]. Dysbiosis can lead to the production of lipopolysaccharides (LPS), a molecule found in the outer membrane of certain bacteria, which can induce low-grade inflammation and contribute to insulin resistance [70]. Dysbiosis is linked to inflammaging [71] and NAFLD [72] as well.

Finally, dysbiosis can contribute to obesity, a key component of metabolic syndrome. Dysbiosis can alter the production of hormones and other molecules that regulate appetite and energy metabolism, leading to increased caloric intake and decreased energy expenditure [68].

Current and emerging strategies for managing metabolic syndrome 

Given the multifaceted nature of metabolic syndrome and its association with the hallmarks of aging, the steps to mitigate its development should also be multi-targeted. There are potential steps that may influence metabolic syndrome and its effects on the hallmarks.

Regular physical activity and a balanced diet rich in fruits, vegetables, lean proteins, and whole grains can help maintain metabolic homeostasis, regulate nutrient sensing, and reduce excess nutrient accumulation in tissues. This can also help reduce obesity [73-75].

Anti-inflammatory diets that are rich in antioxidants and omega-3 fatty acids, or anti-inflammatory medications may help mitigate inflammaging [76]. Metformin and other glucose-lowering drugs can be beneficial in managing deregulated nutrient sensing and improving insulin sensitivity when used under medical supervision [77].

Supplements and interventions that support mitochondrial health, such as Coenzyme Q10 and PQQ, can potentially offset the mitochondrial dysfunction associated with metabolic syndrome [78]. Drugs like senolytics, which selectively remove senescent cells, could be helpful in managing metabolic syndrome [79].

Probiotics, prebiotics, and a diet promoting a healthy gut microbiome can address dysbiosis and reduce its contribution to metabolic syndrome [80]. Although this is a newer area of research, stem cell therapy could potentially help replenish the exhausted stem cell pool and support tissue regeneration and repair [81].

In conclusion, metabolic syndrome significantly intersects with the hallmarks of aging, and studies suggest that metabolic syndrome can accelerate aging by exacerbating these hallmarks.

Effective management and prevention of metabolic syndrome, therefore, could serve as a strategy for promoting healthy aging and delaying the onset of age-related diseases. This underscores the importance of early intervention and the adoption of healthy lifestyles, including a balanced diet and regular physical activity. Future research should continue exploring these critical interactions, ultimately leading to improved therapeutic approaches that address the multifaceted nature of aging and metabolic health.

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