Fight Aging!

Since calorie restriction is the topic for the day so far, I thought I'd finish up by pointing out a recent paper that examines just one of the many concrete benefits that are produced through the practice of calorie restriction. In this case the focus is on blood vessel integrity, and the researchers demonstrate that a low calorie diet in mice reduces the risk of suffering an aneurysm, a localized weakening and consequent distortion of blood vessel walls. Aneurysms in major blood vessels ultimately lead to rupture and bleeding that is far more often fatal than survivable. Larger aneurysms in the brain can cause significant issues even without rupturing because they displace neural tissue, possibly disrupting vital functions as a result.

It isn't too difficult to walk through what is known of the various contributions that increase the risk of aneurysm, and the reasons why that risk rises with age. The first place to start is hypertension, increased blood pressure. Greater pressures means that ever lesser degrees of structural weakness will fail and bulge out into an aneurysm. Hypertension appears to be largely driven by stiffening of blood vessels, as the cardiovascular system reacts incorrectly to the feedback it is given by stiffened vessels. This loss of elasticity is in turn a consequence of cross-linking in the extracellular matrix of blood vessel walls, one of the fundamental forms of damage described in the SENS rejuvenation research portfolio. The normal processes of metabolism generate hardy sugar compounds that can link the complex collagen macromolecules of the extracellular matrix. The structure and movement of those macromolecules determines tissue characteristics such as elasticity, and cross-linking degrades that flexibility to produce stiffening. Other contributions to vascular stiffening include calcification in blood vessel walls and various secondary consequences of the chronic inflammation that accompanies aging, disrupting the signaling involved in blood vessel constriction.

Another group of mechanisms worth emphasizing are those that lead to atherosclerosis: damaged lipids in the bloodstream, such as those produced as a result of the harmful actions of cells with age-related mitochondrial damage, can cause an overreaction when they lodge in blood vessel walls. This produces lesions in which inflammation and immune cell death runs amok, growing into fatty plaques in the blood vessel wall. One of the ways in which such an atherosclerotic plaque can prove fatal is through weakening the blood vessel wall sufficiently for an aneurysm to develop and then rupture. Another is for the plaque to break apart and block a blood vessel elsewhere. Either way, the consequences are unpleasant. To the degree that atherosclerosis is a type of immune overreaction, it is accelerated by the rising levels of chronic inflammation that accompany aging.

Almost all of these processes are modestly reduced in magnitude while an individual is practicing calorie restriction. Inflammation is reduced, mitochondrial function improved, the immune system works more effectively to remove problem cells, and cells do a better job of internal quality control. Other environmental influences on the constriction of blood vessels are improved. Since calorie restriction is known to slow near all measures of aging, it perhaps isn't surprising to see it also reducing aneurysm risk. This is all relative, of course: despite the fact that calorie restriction produces perhaps the largest available long-term benefits for basically healthy individuals, you nonetheless can't reliably diet your way to a life span of a century. Rejuvenation therapies are on the horizon, however, and thus it is perhaps wise to pay attention to the few choices you can make now that are reliable and proven in their effects, likely to add a few years of health to your life span. Missing out by a few years when you could have benefited would be a terrible thing. Unfortunately, beyond calorie restriction and exercise there is little worth the candle at the moment, given the balance of evidence: efforts beyond the health basics are better directed to speeding progress towards human rejuvenation, helping the development of therapies that can repair the molecular damage that causes aging.

Consuming Fewer Calories Reduces the Risk of Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is a localized enlargement of the main artery in the abdomen caused by a weakening of the blood vessel wall. With over three million cases per year in the US, preventing the development of AAA is crucial because, if the aneurysm bursts, the mortality rate can be as high as 80%. The risk of developing AAA increases with age and can be exacerbated by other factors such as smoking. Calorie restriction has been shown to have a variety of health benefits in mice and humans due to its far-reaching effects on the body's metabolism. Researchers wondered whether the risk of AAA might be reduced by a calorie-restricted diet. The researchers placed mice prone to developing AAA on a calorie-restricted diet for 12 weeks and found that the animals were less likely to develop aneurysms than control mice fed a normal diet. The calorie-restricted mice also showed lower rates of AAA rupture and death.

The researchers determined that calorie restriction reduced the levels of an enzyme called MMP2 that degrades the protein matrix surrounding blood vessels. This was because, after 12 weeks of reduced calorie intake, vascular smooth muscle cells in the wall of the aorta up-regulated a metabolic sensor protein called SIRT1, which can epigenetically suppress multiple genes, including MMP2. The researchers found that calorie restriction was unable to reduce MMP2 expression and the incidence of AAA in mice whose vascular smooth muscle cells lack SIRT1. The study suggests that reducing calorie intake can protect mice from AAA by up-regulating SIRT1.

Calorie restriction protects against experimental abdominal aortic aneurysms in mice

Abdominal aortic aneurysm (AAA), characterized by a localized dilation of the abdominal aorta, is a life-threatening vascular pathology. Because of the current lack of effective treatment for AAA rupture, prevention is of prime importance for AAA management. Calorie restriction (CR) is a nonpharmacological intervention that delays the aging process and provides various health benefits. However, whether CR prevents AAA formation remains untested. In this study, we subjected Apoe-/- mice to 12 weeks of CR and then examined the incidence of angiotensin II (AngII)-induced AAA formation. We found that CR markedly reduced the incidence of AAA formation and attenuated aortic elastin degradation in Apoe-/- mice. The expression and activity of Sirtuin 1 (SIRT1), a key metabolism/energy sensor, were up-regulated in vascular smooth muscle cells (VSMCs) upon CR. Importantly, the specific ablation of SIRT1 in smooth muscle cells abolished the preventive effect of CR on AAA formation in Apoe-/- mice. Mechanistically, VSMC-SIRT1-dependent deacetylation of histone H3 lysine 9 on the matrix metallopeptidase 2 (Mmp2) promoter was required for CR-mediated suppression of AngII-induced MMP2 expression. Together, our findings suggest that CR may be an effective intervention that protects against AAA formation.