There are two major subtypes of adipose tissue, i.e., white adipose tissue (WAT) and brown adipose tissue (BAT). It has been known for a long time that WAT mediates obesity and impairs healthful longevity. More recently, interest has focused on BAT, which, unlike WAT, actually augments healthful aging. The goal of this review is to examine the role of BAT in mediating healthful longevity. A major role for BAT and its related beige adipose tissue is thermogenesis, as a mechanism to maintain body temperature by producing heat through uncoupling protein 1 (UCP1) or through UCP1-independent thermogenic pathways. Our hypothesis is that healthful longevity is, in part, mediated by BAT. BAT protects against the major causes of impaired healthful longevity, i.e., obesity, diabetes, cardiovascular disorders, cancer, Alzheimer’s disease, reduced exercise tolerance, and impaired blood flow. Several genetically engineered mouse models have shown that BAT enhances healthful aging and that their BAT is more potent than wild-type (WT) BAT. For example, when BAT, which increases longevity and exercise performance in mice with disruption of the regulator of G protein signaling 14 (RGS14), is transplanted to WT mice, their exercise capacity is enhanced at 3 days after BAT transplantation, whereas BAT transplantation from WT to WT mice also resulted in increased exercise performance, but only at 8 weeks after transplantation. In view of the ability of BAT to mediate healthful longevity, it is likely that a pharmaceutical analog of BAT will become a novel therapeutic modality.

Cellular senescence in cardiomyocytes, characterized by cell cycle arrest, resistance to apoptosis, and the senescence-associated secretory phenotype, occurs during aging and in response to various stresses, such as hypoxia/reoxygenation, ischemia/reperfusion, myocardial infarction (MI), pressure overload, doxorubicin treatment, angiotensin II, diabetes, and thoracic irradiation. Senescence in the heart has both beneficial and detrimental effects. Premature senescence of myofibroblasts has salutary effects during MI and pressure overload. On the other hand, persistent activation of senescence in cardiomyocytes precipitates cardiac dysfunction and adverse remodeling through paracrine mechanisms during MI, myocardial ischemia/reperfusion, aging, and doxorubicin-induced cardiomyopathy. Given the adverse roles of senescence in many conditions, specific removal of senescent cells, i.e., senolysis, is of great interest. Senolysis can be achieved using senolytic drugs (such as Navitoclax, Dasatinib, and Quercetin), pharmacogenetic approaches (including INK-ATTAC and AP20187, p16-3MR and Ganciclovir, p16 ablation, and p16-LOX-ATTAC and Cre), and immunogenetic interventions (CAR T cells or senolytic vaccination). In order to enhance the specificity and decrease the off-target effects of senolytic approaches, investigation into the mechanisms through which cardiomyocytes develop and/or maintain the senescent state is needed.

Introduction: Angiotensin II (AngII) affects cardiovascular health, mediating impacts through AngII type 1 (AT1R) and type 2 (AT2R) receptors. The present study investigated sex and aging-related differences in microvascular AngII receptor function in mice and humans. Methods: Mesenteric resistance arteries (MRA) were isolated from 3-, 12-, and 18-month-old female and male C57/Bl6 mice. Wire myography was used to measure vasoconstriction to AngII and vasodilation to an AT2R agonist (compound 21, C21). Seven healthy adults (3 premenopausal women and 4 age-matched men) were recruited to participate in a study measuring cutaneous microvascular vasoconstriction to AngII in the presence and absence of 10 μM PD123319, an AT2R antagonist. Results: In murine MRA, AngII-induced constriction increases by 18 months in females and by 12 months in males. AT2R-mediated vasodilation was reduced with age in females only, which corresponds with a female-specific decrease in mesenteric AT2R mRNA expression. AT2R inhibition enhances AngII-induced constriction in young female, but not male, mice. Clinical data support that premenopausal women have attenuated AngII constriction vs. men, which is abrogated by AT2R inhibition. AT2R expression is greater in primary aortic smooth muscle cells, but not endothelial cells, from young women compared with men. Conclusions: These data demonstrate enhanced microvascular AT2R function in young female mice and young women. There is a female-specific loss of AT2R function with age in mice, concomitant with declining AT2R expression. These findings implicate AT2R as a sex-specific target for microvascular dysfunction and aging-associated cardiovascular disease.

Introduction: Vascular aging is marked by increased mitochondrial reactive oxygen species (ROS) production, which leads to decreased nitric oxide (NO)-mediated vasodilation. Loss of NO can be partially compensated by endothelium-derived hyperpolarization (EDH), which partly relies on increased mitochondrial Ca²⁺ release to maintain vascular dilation. Thus, intervention in mitochondria may target both NO and EDH signaling to alleviate aging-related vascular dysfunction. DNA damage by mitochondrial ROS is an important cause of organismal aging. Previous work showed that local vascular Ercc1 knockout dramatically accelerates vascular aging. The aim of the study was to investigate the effect of chronic treatment with the modified 6-chromanol, SUL-238, an inhibitor of mitochondrial reverse electron flux and ROS, in a mouse model of accelerated vascular smooth muscle aging induced by DNA repair endonuclease Ercc1 knockout (SMC-KO).

Aim: The aim of the study was to investigate the effect of chronic treatment with the modified 6-chromanol, SUL-238, an inhibitor of mitochondrial reverse electron flux and ROS, in a mouse model of accelerated vascular smooth muscle aging induced by DNA repair endonuclease Ercc1 knockout (SMC-KO).

Methods: SMC-KO mice and healthy wild-type littermates received SUL-238 (90 mg/kg/day) in drinking water from 12 to 22 weeks of age. At the age of 21 weeks, arterial stiffness was measured in vivo with echography and they were euthanized at the age of 22 weeks. Ex vivo vascular function was assessed in wire myography setups and mitochondrial function of the thoracic aorta was assessed using a seahorse assay.

Results: SMC-KO mice showed reduced EDH-mediated vasodilation, elevated arterial stiffness, and increased elastin breaks at 22 weeks of age compared to their wild-type littermates. SUL-238 improved EDH, thus restoring aortic and mesenteric relaxation in SMC-KO mice. Furthermore, the number of elastin breaks was reduced and arterial stiffness normalized after treating SMC-KO mice with SUL-238. Mitochondrial respiration measured in the aorta was not different between the groups.

Conclusion: Chronic treatment with SUL-238 alleviates features of vascular aging, including decreased vasodilation and increased arterial stiffness. SUL-238 seems to have a more general effect on aging rather than involving a direct coupling between mitochondrial function and vascular signaling. SUL-238 is the first small-molecule drug reported to increase EDH after chronic treatment.