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      Validation of anti-aging drugs by treating age-related diseases

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      Publication date (Electronic):
      Journal: Aging
      Publisher: Impact Journals LLC
      Keywords: anti-aging drugs, diseases, cancer, atherosclerosis, resveratrol, rapamycin, metformin

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          Abstract

          Humans die from age-related diseases, which are deadly manifestations of the aging process. In order to extend life span, an anti-aging drug must delay age-related diseases. All together age-related diseases are the best biomarker of aging. Once a drug is used for treatment of any one chronic disease, its effect against other diseases (atherosclerosis, cancer, prostate enlargement, osteoporosis, insulin resistance, Alzheimer's and Parkinson's diseases, age-related macular degeneration) may be evaluated in the same group of patients. If the group is large, then the anti-aging effect could be validated in a couple of years. Startlingly, retrospective analysis of clinical and preclinical data reveals four potential anti-aging modalities.

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          Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway.

          Pankaj Kapahi, Brian M. Zid, Tony Harper … (2004)
          In many species, reducing nutrient intake without causing malnutrition extends lifespan. Like DR (dietary restriction), modulation of genes in the insulin-signaling pathway, known to alter nutrient sensing, has been shown to extend lifespan in various species. In Drosophila, the target of rapamycin (TOR) and the insulin pathways have emerged as major regulators of growth and size. Hence we examined the role of TOR pathway genes in regulating lifespan by using Drosophila. We show that inhibition of TOR signaling pathway by alteration of the expression of genes in this nutrient-sensing pathway, which is conserved from yeast to human, extends lifespan in a manner that may overlap with known effects of dietary restriction on longevity. In Drosophila, TSC1 and TSC2 (tuberous sclerosis complex genes 1 and 2) act together to inhibit TOR (target of rapamycin), which mediates a signaling pathway that couples amino acid availability to S6 kinase, translation initiation, and growth. We find that overexpression of dTsc1, dTsc2, or dominant-negative forms of dTOR or dS6K all cause lifespan extension. Modulation of expression in the fat is sufficient for the lifespan-extension effects. The lifespan extensions are dependent on nutritional condition, suggesting a possible link between the TOR pathway and dietary restriction.
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            Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.

            Jill Milne, Philip Lambert, Simon Schenk … (2007)
            Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.
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              Genetics: influence of TOR kinase on lifespan in C. elegans.

              Tibor Vellai, Krisztina Takács-Vellai, Yue Zhang … (2003)
              Article 0 comments Cited 330 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Aging (Albany NY)
                Journal ID (publisher-id): ImpactJ
                Title: Aging
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1945-4589
                Publication date Collection: March 2009
                Publication date (Electronic): 28 March 2009
                Volume: 1
                Issue: 3
                Pages: 281-288
                Affiliations
                Cancer Center, Ordway Research Institute, Albany, NY 12208, USA
                Author notes
                Correspondence: Mikhail V. Blagosklonny, MD, PhD, Roswell Park Cancer Institute, Elm St., Buffalo, NY 14203, USA Blagosklonny@ 123456oncotarget.com
                Article
                DOI: 10.18632/aging.100034
                PMC ID: 2806014
                PubMed ID: 20157517
                SO-VID: 40e03cf3-b8f6-4d9a-add3-e1f495bc5c5d
                Copyright © Copyright: ©2009 Blagosklonny.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 20 September 2008
                Date accepted : 28 March 2009
                Categories
                Subject: Review

                ScienceOpen disciplines: Cell biology
                Keywords: cancer,diseases,atherosclerosis,anti-aging drugs,rapamycin,metformin,resveratrol
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: cancer, diseases, atherosclerosis, anti-aging drugs, rapamycin, metformin, resveratrol

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