Protective Effect of the Inhibition of the Renin-Angiotensin System on Aging
Although recent economic events may have focused decision-making and planning attention on the short term, in the longer term there is still life extension. Evidence is mounting that inhibiting the renin-angiotensin system may be a way to prevent many deleterious effects of aging. As the authors of one recent paper note: “Experimental studies indicate that long-term inhibition of the renin-angiotensin system (RAS) can prevent most of the deleterious effects due to aging in the cardiovascular system and in the kidney of the normal mouse and rat.”1
Angiotensin converting enzyme (ACE) inhibitors and angiotensin II nonpeptide type 1 receptor (AT1) blockers are currently used widely to treat hypertension, which induces cardiovascular changes (enhanced stiffness, hyperplasia, and collagen accumulation) that are also observed in aging. “The similarities between aging and hypertension added to the fact that increased BP [blood pressure] is usually observed in aged humans and rats, suggest the possibility that hypertension could be a form of accelerated aging.”
Kidney failure is a frequent cause of death in rodents and decline of the kidney’s filtering ability is a usual feature in human aging. Glomerulosclerosis, a process that commonly occurs in the aging kidney and in various models of kidney injury can be effectively treated with ACE inhibitors as well as by AngII antagonists. (AngII binds to the AT1 receptor.) In one study reported by the authors of ref 1, chronic ACE inhibitor treatment during the entire lifespan of the rat reduced proteinuria and albumin accumulation in podocytes (a type of epithelial cell in the kidney), delayed the progression of glomerulosclerosis and prevented the age-related hypertrophy of the mesangial domain [thickening of the basement membrane, as also occurs normally in human kidney aging] of the glomeruli.2 Similarly, treatment with ACE inhibitors or AngII antagonists abolished the increase in blood pressure seem in untreated rats and also delayed cardiac and left ventricular hypertrophy/hyperplasia and aortic growth.1 Moreover, other animal studies have shown that these drugs can increase the production of nitric oxide by preserving NOS (nitric oxide synthase) activity in endothelial cells of elastic arteries. The treatments have even been shown to reduce anxiety, and improve learning, memory and motor performance in the aged rat.3
Improvement in Endothelial Function in Penile Tissue of Mice
Another recent paper3A even reported improvement of penile endothelial function of the corpus cavernosum in apolipoprotein E knockout mice (a widely used animal model of the development of human atherosclerosis) treated with an angiotensin receptor blocker drug, irbesartan. “The local synthesis of angiotensin II in the corpus cavernosum initiating the detumescence phase in humans could be responsible.”3A This suggests that angiotensin II might be a cause of human erectile dysfunction.
Life Extension in Mice with Disrupted Angiotensin Receptor
A new study4 now reports that targeted disruption of the gene that encodes AT1A results in a 26% increase in lifespan in mice compared to wild-type mice. The treated animals developed less cardiac and vascular injury, and multiple organs showed less oxidative damage as compared to the untreated (wild-type) animals. The authors report that the treated mice had more mitochondria and upregulation of two longevity associated genes, nicotinamide phosphoribosyltransferase (Nampt) and sirtuin 3 (Sirt3) in the kidney. The mice with the disrupted AT1A gene substantially outlived the wild type mice. “At 29 months, when all wild-type animals [had] died, 17 AT1A-deficient mice (85%) were still alive These remaining mice lived for an additional 7 months.”4
Renin-Angiotensin System and Muscle Function
As we have written before in this newsletter, studies in humans suggest that ACE inhibitors may halt or slow decline in muscle strength in elderly
Improved Vascular Function In Rheumatoid Arthritis Patients
A recent paper7 also reports that ACE inhibition improved vascular function in rheumatoid arthritis patients (who are at increased risk of cardiovascular disease), despite the fact that systolic blood pressure and heart rate were unchanged in the study and diastolic blood pressure decreased only slightly. There was, however, an increase in flow-mediated dilation, indicating improved endothelial function.
Vitamin D as a Possible Modulator of the Renin-Angiotensin System
Finally, an interesting recent paper8 reports that
1. Basso et al. Protective effect of the inhibition of the renin-angiotensin system on aging. Regul Pept 128:247-52 (2005).
2. Hendes et al. Effect of chronic ANG I-converting enzyme inhibition on aging processes: I. Kidney structure and function. Am J Physiol 266:R1038-51 (1994).
3. Basso et al. Long-term inhibition of the renin-angiotensin system improves spatial working memory in the rat. J Hypertens 18(Suppl. 4):S77 (2000).
3A. Baumhäkel et al. Improvement of endothelial function of the corpus cavernosum in apolipoprotein E knockout mice treated with irbesartan. J Pharmacol Exp Ther327(3):692-8 (2008).
4. Benigni et al. Disruption of the Ang II type 1 receptor promotes longevity in mice. J Clin Invest 119(3):524-30 (2009).
5. Carter et al. Angiotensin-converting enzyme inhibition intervention in elderly persons: effects on body composition and physical performance. J Gerontol A Biol Sci Med Sci 60A(11):1437-46 (2005).
6. Onder et al. Relation between use of angiotensin-converting enzyume inhibitors and muscle strength and physical function in older women: an observational study. Lancet 359:926-30 (2002).
6A. Di Bari et al. Antihypertensive medications and differences in muscle mass in older persons: the Health. Aging and Body Composition Study. J Am Geriatr Soc 52:961-6 (2004).
6B. Williams et al. The ACE gene and muscle performance. Nature 403:614 (2000).
7. Flammer et al. Angiotensin-converting enzyme inhibition improves vascular function in rheumatoid arthritis. Circulation 117:2262-9 (2008).
8. Yuan et al. 1.25-dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter. J Biol Chem282(41):29821-30 (2007)
9. Renin inhibition reduces hypercholesterolemia-induced atherosclerosis in mice. J Clin Invest 118(3):984-92 (2008).
10. Actis-Goretta et al. Inhibition of angiotensin converting enzyme (ACE) activity by flavan-3-ols and procyanidins. FEBS Lett 555:597-600 (2003).
11. Aviram and Dornfeld. Pomegranate juice consumption inhibits serum angiotensin converting enzyme activity and reduces systolic blood pressure. Atherosclerosis 158:195-8 (2001).
12. Schaffer et al. Interaction between the actions of taurine and angiotensin II. Amino Acids 18:305-18 (2000).