Introduction

The metabolic syndrome (MS) is a cluster of disorders of lipid and glucose metabolism, which are important risk factors for the development of atherosclerosis, cardiovascular diseases (CVD), and type-2 diabetes mellitus. Especially vulnerable are elderly populations and MS has become an important risk factor for cardiovascular morbidity and mortality, including stroke and both coronary heart disease (CHD). The prevalence and severity of MS are affected by factors such as ethnicity, gender, lifestyle, age etc which adds a layer of complexity to this condition that presents a modern day challenge to medicine.

MS has been an increasing area of focus for the past several decades, because of the prevalence of the obesity epidemic and is characterized by increased levels of adipose tissue and triglycerides in the blood stream. These features highlight age as an independent risk factor for the metabolic syndrome, which may aggravate the burden of CVD and diabetes in the elderly population.

Mechanisms of Aging and MS Connection

Although MS is generally recognized as a process that speeds up aging, the mechanisms underpinning these processes have yet to be fully elucidated. There is emerging evidence that longevity-associated genes are important. ~ October 2023 (periodic) Experimental models that manipulate major lifespan-regulating pathways, including the sirtuins, p66Shc and the mTOR signalling pathway, have demonstrated, with varying success, that such manipulations are capable of inducing in mice an MS-like condition. Other pathways, such as insulin and IGF-1 signaling and FOXO transcription factors, continue to associate nutrient availability and lifespan with metabolic wellness.

Mitochondrial Dysfunction in Pathophysiological Perspective

Central for MS pathophysiology is systemic mitochondrial dysfunction induced by MS. Dysfunction of oxidative phosphorylation, mitochondrial biogenesis, and insulin signaling lead to loss of energy homeostasis. In the myocardium, such alterations stimulate lower energetic efficiency, with impaired diastolic function and lipid deposition which predisposes to metabolic cardiomyopathy.

In addition, the hyperactivation of renin-angiotensin-aldosterone system (RAS) increases oxidative stress, which promotes mitochondrial apoptosis and bioenergetic disorders. In summary, the interplay of genetic, environmental, and aging factors induces mitochondrial abnormalities that are further exacerbated by genetic, environmental, and aging factors, and that will in turn perpetuate insulin resistance, glucose dysregulation, and cardiac dysfunction.

Oxidative Stress and Free Radicals

Oxidative stress, orchestrated by free oxygen radicals, is a critical determinant underlying the pathogenesis of MS-related complications. Ischemic conditions induce not only structural damage in myocardial cells, a major source of free radicals, but also most of these structures are injured more severely in ischemia/reperfusion. This assault causes oxidation of electron-transport complexes, inhibits adenosine triphosphate production and disrupts mitochondrial status leading to progressive organ injury.

Experimental models show that hypertriglyceridemia and hypertension worsen myocardial vulnerability in ischemia-reperfusion injury. Investigational drugs that reduce oxidative stress (eg, free radical scavengers) have been reported to reduce cardiac arrhythmias and protect myocardial function.

Sex Differences and Antioxidant Defenses

These two factors make the MS / oxidative stress equation even more ambiguous. Men have lower levels of antioxidant enzymes, such as superoxide dismutase and catalase, also compared to women. Females show relatively higher antioxidant potential, which is aggravated by aging. Such discrepancies underline the importance of gender-directed approaches in therapeutic strategies that take into account MS comorbidity-related vulnerabilities.

Ch02 Experimental Models and Insights into MS Pathophysiology

Novel animal models, including sugar-inducible hypertriglyceridemic and hypertensive rats, can potentially help elucidate MS-related dysregulation. These models demonstrate endothelial dysfunction, accelerated vascular senescence and impaired myocardial recovery after ischaemia. Indeed, MS animals presented more frequent ventricular arrhythmias and higher levels of oxidative damage in the reperfusion period confirming the importance of antioxidant defenses in preventing these consequences.

What You Can Do to Prevent and Promote Healthy Aging

So what can you do to prevent and or manage MS to promote healthy aging and a lower risk for age-related cardiovascular diseases? Population-based studies underline the need for early measures against components of MS in the middle-aged and older people. Dieting, lifestyle changes, and medications focused on strengthening mitochondrial performance and decreasing oxidative stress to improve metabolic flexibility are fundamental.

Conclusion

Oxidative stress, mitochondrial dysfunction and altered metabolic signaling are interconnected between aging and metabolic syndromeה. The foundation for minimizing MS sequelae and maximizing longevity lies in treatment strategies directed at these underlying mechanisms. Gaining insight into the gender-specific and molecular nuances of MS will enable bespoke interventions that could promote healthier aging trajectories, especially in vulnerable populations.