Rapamycin extends murine lifespan but has limited effects on aging.

Aging is a major risk factor for a large number of disorders and functional impairments. Therapeutic targeting of the aging process may therefore represent an innovative strategy in the quest for novel and broadly effective treatments against age-related diseases. The recent report of lifespan extension in mice treated with the FDA-approved mTOR inhibitor rapamycin represented the first demonstration of pharmacological extension of maximal lifespan in mammals. Longevity effects of rapamycin may, however, be due to rapamycin's effects on specific life-limiting pathologies, such as cancers, and it remains unclear if this compound actually slows the rate of aging in mammals. Here, we present results from a comprehensive, large-scale assessment of a wide range of structural and functional aging phenotypes, which we performed to determine whether rapamycin slows the rate of aging in male C57BL/6J mice. While rapamycin did extend lifespan, it ameliorated few studied aging phenotypes. A subset of aging traits appeared to be rescued by rapamycin. Rapamycin, however, had similar effects on many of these traits in young animals, indicating that these effects were not due to a modulation of aging, but rather related to aging-independent drug effects. Therefore, our data largely dissociate rapamycin's longevity effects from effects on aging itself.

Usefulness of percutaneous aortic valve implantation to improve quality of life in patients >80 years of age.

Older patients with aortic stenosis cannot always be offered conventional surgical aortic valve replacement at an acceptable risk. Transcatheter aortic valve implantation (TAVI) is currently considered an alternative treatment option with lower periprocedural risks. However, its effect on post-TAVI quality of life and clinical improvement has not been systematically and prospectively evaluated in those of advanced age. Thus, the aim of the present study was to assess the clinical improvement in geriatric patients after TAVI, with a special emphasis on quality of life. In the present study, we assessed the quality of life and brain natriuretic peptide in patients aged >80 years, before and 6 months after transfemoral CoreValve implantation. Of 87 prospectively studied patients with severe, symptomatic aortic stenosis at an age of ≥81 years, 80 survived for 6 months and were able to attend the follow-up visit with a quality of life assessment, using the Medical Outcomes Trust Short Form 36-Item Health Survey (average age 86 ± 2.9 years). The average scores of all 8 health components had improved significantly after TAVI. The greatest gain was seen in physical functioning (improvement from 23.4 ± 6.0 to 67.8 ± 13.7; p <0.001). The lowest gain was seen in bodily pain (improved from 37.5 ± 9.4 to 51.3 ± 11.5; p <0.05). Similarly, both the physical and the mental component summary scores improved significantly. This was consistent with significant improvement in brain natriuretic peptide levels (5,770 ± 8,016 to 1,641 ± 3,650 ng/L; p <0.0001). In conclusion, the results of the present study have shown a significant clinical benefit from TAVI in a patient population aged ≥81 years.

Interstitial fibrosis and microvascular disease of the heart in uremia: amelioration by a calcimimetic.

In patients with chronic renal failure, the heart undergoes remodeling, characterized by hypertrophy, fibrosis, and capillary/myocyte mismatch. In this study, we observed the effects of the calcimimetic agent R-568 on microvascular disease and interstitial fibrosis of the heart. Three-month-old male Sprague-Dawley rats were randomized to subtotal nephrectomy (SNX) or sham operation and subsequently received vehicle or R-568 under two experimental protocols, one for 1 month and the other for 3 months. Echocardiography, capillary length density, volume density of interstitial tissue, and immunohistochemistry and western blots (calcium-sensing receptor, collagen I and III, transforming growth factor (TGF)-beta, mitogen-activated protein kinases, and nitrotyrosine) were assessed. After SNX, weight and wall thickness of the left and the right ventricle were elevated. The ratio of heart to body weight and interventricular septum thickness were not changed by R-568 treatment. The left ventricle fractional shortening (by echocardiography) was lower in SNX; this was ameliorated by R-568. Reduced capillary length density and increased interstitial fibrosis in SNX were improved by R-568, which also reduced the expression of TGF-beta, and collagen I and III. The calcimimetic increased the activation of ERK-1/2, normalized p38 and JNK signaling, and prevented oxidative stress. We conclude that lowering parathyroid hormone with a calcimimetic significantly improves cardiac histology and function but not the left ventricular mass in SNX.