The vascular system does not age gracefully. Blood vessel walls become stiff and inflamed, interfering in contraction and dilation in response to circumstances. The result is the raised blood pressure of hypertension, which causes damage throughout the body in numerous ways. Further, the fatty lesions of atherosclerosis form in later life, weakening and narrowing blood vessels. This is the result of increased levels of oxidized cholesterol molecules, causing the macrophages responsible for cleaning up blood vessel wall tissues to falter in their tasks. Further still, the blood-brain barrier that lines blood vessels in the brain breaks down and leaks unwanted cells and molecules into brain tissue, causing neuroinflammation and the onset of cognitive decline. But there is more than even this, such as the loss of capillary network density that leads to a declining supply of nutrients and oxygen to tissues throughout the body.
Today's short open access paper is a brief tour of a few strategies for which there is evidence for their application to reduce the impact of vascular aging. It is a mixed bag in terms of size of effect, reliability, and quality and amount of evidence. The best of the bunch is likely senolytic therapies that selectively destroy senescent cells, but even here, while the animal data is quite impressive, that outcome remains to be proven in human trials. The point to take away from this is that the aging of the vascular system is quite important in the progression of degenerative aging. A great many issues lie downstream of hypertension, blood-brain barrier dysfunction, and the other manifestations of vascular aging, and so successful interventions will be broadly beneficial.
Classical strategies targeting mechanisms of vascular aging to delay vascular aging and prevent disease, such as exercise, diet, and other lifestyle interventions, have far-reaching significance. However, these alone seem to be insufficient to prevent the occurrence of geriatric disease and efforts are needed to tackle the underlying processes of vascular aging. At present, the most promising novel strategies for delaying vascular aging include improving the function of mitochondria, reducing age-related inflammation, increasing autophagy, moderately reducing the activity of the nutrient-sensing network, especially reducing the activity of mammalian target of rapamycin complex 1 (mTORC1), removing senescent cells, and using its own endogenous metabolites to re-energize stem cells, and so forth. Several potential drugs and natural products have been reported to modulate aging. Shedding light on the mechanisms of vascular aging and the development of novel agents will likely reduce the risk of age-related disease and extend the human health span.
Senolytics is a class of drugs that selectively kill senescent cells, and scientists have reported the first senolytics drug combination - dasatinib + quercetin. Recent studies demonstrated that senolytic treatment exerted a positive effect on senescent cell burden, DNA damage, vasomotor function, nitric oxide signaling, calcification, and osteogenic signaling in chronologically aged mice. Another study indicated that this combination selectively cleared senescent cells in idiopathic pulmonary fibrosis mice and improved lung function and physical health indicators in mice. In an open-labeled phase I clinical trial, nine patients with diabetic nephropathy received dasatinib and quercetin therapy, which reduced the load of adipose tissue senescent cells. The effect of senolytic treatment may be mediated by members of the BCL-2 family, PI3K/AKT, p53/FOXO4, HSP90, and HIF1α. These results proved that senolytics are expected to be used to delay vascular aging and prolong the life span of the elderly.
Metformin is a biguanide drug widely used for type 2 diabetes. A study on mice found that treatment with metformin mimics some of the benefits of calorie restriction, such as increased insulin sensitivity and reduced low-density lipoprotein and cholesterol levels and finally improves health span and life span. Retrospective, epidemiological analyses elucidated that administration of metformin is associated with the improvement of vascular function and reductions in the incidence and mortality of ischemic disease. The results of metformin treatment in age-related disease are also encouraging, with a wide range of protective roles in cardiovascular disease, cerebrovascular disease, cancer, chronic kidney disease, and neurodegeneration.
Studies showed that rapamycin destabilizes and inhibits mTORC1, which is an important molecule regulating various cellular processes. It was proposed that rapamycin extended the life span by up to 60% and even reversed the changes in vascular function and structure, cognition, cardiac hypertrophy, and immune senescence in aged mice, through both genetic and pharmacological modulation of mTOR signaling. The current clinical uses of rapamycin may be limited by its adverse effect to some extent, including hyperglycemia and hyperlipidaemia. As an effective anti-vascular aging agent, rapamycin has both advantages and disadvantages and it should be balanced for every individual.
Nicotinamide adenine dinucleotide and sirtuins
Nicotinamide adenine dinucleotide (NAD+), as a cofactor in many key biological processes of cells, is an important mediator of biochemical reactions in the body and an essential molecule in many metabolic pathways. It has been found that the concentration of NAD+ in human tissues gradually decreases with age, and at least decreases by 50%, accompanied by a series of pathological processes, such as chronic inflammation, oxidative stress, DNA damage, and mitochondrial dysfunction. Supplementation of NAD+ and its precursors is beneficial to reduce the occurrence of oxidative stress, increase the regenerative capacity of vascular endothelial cells, and prolong cell life.
Berberine is an isoquinoline alkaloid extracted from various plants, which plays an important role in lowering blood pressure, regulating blood lipids, and controlling blood glucose. It was found that berberine could activate the AMPK-signaling pathway, and inhibit the activity of mTOR to delay cell senescence caused by DNA replication disorder, and also increase antioxidant activity by activating the NRF2-signaling pathway to achieve the effect of longevity extension.
Nucleoside reverse transcriptase inhibitors
Nucleoside reverse transcriptase inhibitors (NRTIs) are used in clinical HIV treatment, but can also inhibit open-reading frame-related reverse transcriptase activity of long dispersive elements. Recent studies have found that NRTIs, including lamivudine and stavudine, can reduce senescence-related secretory phenotypes and inflammatory responses in older mice. These findings make NRTIs a new candidate for delaying aging.
Remote ischemic preconditioning
Remote ischemic preconditioning (RIPC) is a safe, noninvasive, simple, and low-cost non-drug device intervention and has been widely used since it was first proposed. RIPC is an intrinsic protective phenomenon to protect the vital organs with non-fatal regional ischemia followed by reperfusion, through the involvement of SDF-1α, HIF-1α, oxidative stress, and apoptotic pathways. A recent study has demonstrated that 1-month RIPC treatment can significantly reduce the blood pressure of patients with mild essential hypertension and improve microvascular endothelial function.