Fight Aging!

Age is characterized by a growing degree of unprompted, unresolved inflammation. Inflammation is a rousing of the immune system into action, a necessary process that aids in the defense of the body against pathogens, as well as in regeneration of injuries. In youth, inflammation is near always promptly resolved once the need is passed. In old age, however, inflammation becomes constant, triggered by many distinct causes: persistent infections; metabolic waste; the breakdown of the intestinal barrier and the blood-brain barrier, leaking unwanted molecules, cells, and pathogens; and rising numbers of senescent cells that secrete inflammatory signals.

Constant, unresolved inflammation is disruptive of tissue maintenance and function throughout the body. In recent years, the research community has demonstrated quite conclusively that accumulation of senescent cells in old tissues causes a significant fraction of this chronic inflammation of aging. Targeted removal of as few as a third of the senescent cells present in tissue via senolytic therapies reduces inflammatory signaling and reverses many of its consequences. This has been amply demonstrated in mice, but human trials of first generation senolytic drugs have to date only assessed a few conditions and a few different approaches to destruction of senescent cells.

As noted in today's open access paper, inflammation and cellular senescence is important in the vascular stiffening and thickening of age, a process that contributes to hypertension and all of the major damage to tissues and systems in the body and brain then caused by chronically raised blood pressure. Interestingly, it is possible to link increased levels of cellular senescence in blood vessel walls with the presence of advanced glycation end-products (AGEs), sugary metabolic waste that forms cross-links between collagen and other molecules of the extracellular matrix, changing the structural properties of tissue as a result. Reduced elasticity (i.e. stiffening) is one direct consequence, but these changes also likely cause nearly cells to react in ways that increase the burden of cellular senescence in that tissue.

Proinflammation, profibrosis, and arterial aging

Aging is a major risk factor for the morbidity and mortality of quintessential cardiovascular diseases, such as hypertension and atherosclerosis, mainly due to arterial wall structural and functional adverse remodeling, such as intimal medial thickening (IMT) and stiffening. The age-associated increase in collagen deposition within the arterial wall is known as arterial profibrosis; and the age-associated increase in sterile inflammation within the wall is known as arterial proinflammation. Proinflammation and profibrosis are the key molecular and cellular events in age-associated IMT and arterial stiffening. It is widely accepted that proinflammatory endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) are mainly responsible for age-associated adverse arterial cellular events; however, the consequence of proinflammation and profibrosis (predisposing collagen deposition) greatly affects the behavior of these cells adversely with a predominant impact on the age-associated arterial stiffening, which is not completely understood.

In the aging arterial wall, collagen types I, II, and III are predominant, and are mainly produced by stiffened vascular smooth muscle cells (VSMCs) governed by proinflammatory signaling, leading to profibrosis. Profibrosis is regulated by an increase in the proinflammatory molecules angiotensin II, milk fat globule-EGF-VIII, and transforming growth factor-beta 1 (TGF-β1) signaling and a decrease in the vasorin signaling cascade. The release of these proinflammatory factors triggers the activation of matrix metalloproteinase type II (MMP-2) and activates profibrogenic TGF-β1 signaling, contributing to profibrosis. The age-associated increase in activated MMP-2 cleaves latent TGF-β and subsequently increases TGF-β1 activity leading to collagen deposition in the arterial wall.

Collagen fibrils become resistant to cleavage over time. Mice with a targeted mutation that yields collagenase-resistant type I collagen create an old senescent phenotype. VSMCs in the aortic wall of these mutated mice are susceptible to stress-induced cellular senescence, displaying senescence-associated beta-galactosidase (SA-β-Gal) activity and upregulated p16 in response to angiotensin II infusion. In addition, mutant collagen directly reduces the replicative lifespan of human VSMCs and increases stress-induced measures of cellular senescence such as SA-β-Gal activity, p16 expression, and p21 expression. Thus, resistance to collagen cleavage, such as advanced glycation endproduct (AGE) formation, accelerates cellular senescence, arterial stiffening, and aging. A long-term senolytic treatment (intermittently with dasatinib + quercetin via oral gavage) significantly eliminates senescent cells in the medial layer of aortae from aged mice and reduces arterial stiffening.