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Prospective Treatment of Age-Related Diseases by Slowing Down Aging

2012; Elsevier BV; Volume: 181; Issue: 4 Linguagem: Inglês

10.1016/j.ajpath.2012.06.024

1525-2191

Mikhail V. Blagosklonny,

Dietary Effects on Health

Atherosclerosis, hypertension, obesity, diabetic complications, cancer, benign prostate hyperplasia, Alzheimer and Parkinson diseases, age-related macular degeneration, osteoarthritis, osteoporosis, and seborrheic keratosis are strongly associated with aging, implying a common underlying process. Each disease is treated separately and, in most cases, symptomatically. Suppression of aging itself should delay or treat all age-related diseases, thus increasing healthy life span and maximal longevity. But, is it possible to slow down aging? Recent evidence indicates that the target of rapamycin signaling pathway is involved in cellular senescence and organismal aging. Preclinical and clinical studies demonstrated the therapeutic effects of rapamycin in diverse age-related diseases. One simple reason why a single drug is indicated for so many age-related diseases is that it inhibits the aging process. Atherosclerosis, hypertension, obesity, diabetic complications, cancer, benign prostate hyperplasia, Alzheimer and Parkinson diseases, age-related macular degeneration, osteoarthritis, osteoporosis, and seborrheic keratosis are strongly associated with aging, implying a common underlying process. Each disease is treated separately and, in most cases, symptomatically. Suppression of aging itself should delay or treat all age-related diseases, thus increasing healthy life span and maximal longevity. But, is it possible to slow down aging? Recent evidence indicates that the target of rapamycin signaling pathway is involved in cellular senescence and organismal aging. Preclinical and clinical studies demonstrated the therapeutic effects of rapamycin in diverse age-related diseases. One simple reason why a single drug is indicated for so many age-related diseases is that it inhibits the aging process. Humans and other mammals often die from age-related diseases, such as cancer, ischemic heart disease, hypertension, stroke, and complications of osteoporosis, type 2 diabetes mellitus, and Alzheimer and Parkinson diseases. Each disease is treated separately, for example, diabetes is commonly treated with insulin. However, insulin does not treat cancer; instead, it stimulates cancer.1Berstein L.M. Metformin, insulin, breast cancer and more.Future Oncol. 2009; 5: 309-312Crossref PubMed Scopus (19) Google Scholar Furthermore, insulin promotes obesity and atherosclerosis,1Berstein L.M. Metformin, insulin, breast cancer and more.Future Oncol. 2009; 5: 309-312Crossref PubMed Scopus (19) Google Scholar and insulin therapy likely worsens retinopathy.2Henricsson M. Janzon L. Groop L. Progression of retinopathy after change of treatment from oral antihyperglycemic agents to insulin in patients with NIDDM.Diabetes Care. 1995; 18: 1571-1576Crossref PubMed Scopus (49) Google Scholar In addition, insulin-activated pathways promote aging.3Bartke A. Insulin and aging.Cell Cycle. 2008; 7: 3338-3343Crossref PubMed Scopus (108) Google Scholar, 4Barzilai N. Huffman D.M. Muzumdar R.H. Bartke A. The critical role of metabolic pathways in aging.Diabetes. 2012; 61: 1315-1322Crossref PubMed Scopus (518) Google Scholar Therefore, while compensating for insulin insufficiency and insulin resistance in diabetes, insulin therapy may accelerate aging. Similarly, while treating cancer, radiation does not treat diabetes and other age-related diseases, if cancer were to be cured, other diseases would continue to limit life span. To prevent age-related diseases and, therefore, to extend healthy and maximal life span, it is necessary to slow down the aging process. Mammalian target of rapamycin (mTOR) is a cytoplasmic kinase that regulates cell growth and metabolism.5Wullschleger S. Loewith R. Hall M.N. TOR signaling in growth and metabolism.Cell. 2006; 124: 471-484Abstract Full Text Full Text PDF PubMed Scopus (4671) Google Scholar The mTOR pathway is activated by mitogens (eg, insulin-like growth factor-1 and insulin) and nutrients (amino acids, glucose, and fatty acids), hormones, and oncogenic proteins (eg, Ras, Raf, MEK, phosphatidylinositol 3-kinase, and Akt; Figure 1). The mTOR pathway stimulates cell growth (causing cell hypertrophy), ribosome biogenesis, and protein synthesis (including aggregation-prone proteins) and inhibits digestion of defective mitochondria and aggregation-prone proteins.5Wullschleger S. Loewith R. Hall M.N. TOR signaling in growth and metabolism.Cell. 2006; 124: 471-484Abstract Full Text Full Text PDF PubMed Scopus (4671) Google Scholar In proliferating cells, active mTOR stimulates cellular mass growth and metabolism. When the cell cycle is arrested, still active mTOR causes hypertrophy and, eventually, cellular senescence,6Demidenko Z.N. Blagosklonny M.V. Growth stimulation leads to cellular senescence when the cell cycle is blocked.Cell Cycle. 2008; 7: 3355-3361Crossref PubMed Scopus (285) Google Scholar, 7Demidenko Z.N. Zubova S.G. Bukreeva E.I. Pospelov V.A. Pospelova T.V. Blagosklonny M.V. Rapamycin decelerates cellular senescence.Cell Cycle. 2009; 8: 1888-1895Crossref PubMed Scopus (342) Google Scholar, 8Leontieva O.V. Blagosklonny M.V. DNA damaging agents and p53 do not cause senescence in quiescent cells, while consecutive re-activation of mTOR is associated with conversion to senescence.Aging (Albany NY). 2010; 2: 924-935PubMed Google Scholar characterized by large-cell morphological features and irreversible loss of proliferative/regenerative potential. The process of conversion of reversible arrest into senescence is termed geroconversion.9Blagosklonny M.V. Cell cycle arrest is not yet senescence, which is not just cell cycle arrest: terminology for TOR-driven aging.Aging (Albany NY). 2012; 4: 159-165PubMed Google Scholar Rapamycin and other inhibitors of the mTOR pathway decelerate geroconversion in cell culture.7Demidenko Z.N. Zubova S.G. Bukreeva E.I. Pospelov V.A. Pospelova T.V. Blagosklonny M.V. Rapamycin decelerates cellular senescence.Cell Cycle. 2009; 8: 1888-1895Crossref PubMed Scopus (342) Google Scholar, 10Demidenko Z.N. Korotchkina L.G. Gudkov A.V. Blagosklonny M.V. Paradoxical suppression of cellular senescence by p53.Proc Natl Acad Sci U S A. 2010; 107: 9660-9664Crossref PubMed Scopus (240) Google Scholar, 11Leontieva O. Gudkov A. Blagosklonny M. Weak p53 permits senescence during cell cycle arrest.Cell Cycle. 2010; 9: 4323-4327Crossref PubMed Scopus (116) Google Scholar Rapamycin also prevents hyperactivation and exhaustion of stem cells in the organism,12Gan B. Sahin E. Jiang S. Sanchez-Aguilera A. Scott K.L. Chin L. Williams D.A. Kwiatkowski D.J. DePinho R.A. mTORC1-dependent and -independent regulation of stem cell renewal, differentiation, and mobilization.Proc Natl Acad Sci U S A. 2008; 105: 19384-19389Crossref PubMed Scopus (174) Google Scholar, 13Chen C. Liu Y. Zheng P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells.Sci Signal. 2009; 2 (ra75)Google Scholar and it reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells.14Cao K. Graziotto J.J. Blair C.D. Mazzulli J.R. Erdos M.R. Krainc D. Collins F.S. Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells.Sci Transl Med. 2011; 3 (89ra58)Google Scholar In arrested cells, mTOR increases cell size, differentiation, and differentiation-related cellular functions. Therefore, senescent/gerogenic cells with active mTOR are hypertrophic and hyperfunctional or hyperactive.9Blagosklonny M.V. Cell cycle arrest is not yet senescence, which is not just cell cycle arrest: terminology for TOR-driven aging.Aging (Albany NY). 2012; 4: 159-165PubMed Google Scholar Functions of differentiated cells are tissue type specific. For example, fibroblasts, adipocytes, and immune cells secrete cytokines. Therefore, hyperfunctional fibroblasts, adipocytes, and immune cells cause pro-inflammation and fibrosis. Moreover, mTOR is involved in the hypersecretory phenotype of senescent cells.15Narita M. Young A.R. Arakawa S. Samarajiwa S.A. Nakashima T. Yoshida S. Hong S. Berry L.S. Reichelt S. Ferreira M. Tavare S. Inoki K. Shimizu S. Spatial coupling of mTOR and autophagy augments secretory phenotypes.Science. 2011; 332: 966-970Crossref PubMed Scopus (397) Google Scholar As another example, hyperfunctional osteoclasts resorb the bone, thus potentially causing osteoporosis. Liver cells produce lipoproteins, contributing to accumulation of lipids in the arterial wall; and platelets aggregate, leading to thrombosis. For example, atherosclerosis depends on hyperfunctions of local cells [endothelial cells, smooth muscle cells (SMCs), and macrophages] and distant cells (hepatocytes, bone marrow cells, and adipocytes). Atherosclerosis is associated with hypertrophy of arterial SMCs and activation of macrophages in the arterial wall.16Orlandi A. Bochaton-Piallat M.L. Gabbiani G. Spagnoli L.G. Aging, smooth muscle cells and vascular pathobiology: implications for atherosclerosis.Atherosclerosis. 2006; 188: 221-230Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 17Siegel-Axel D. Daub K. Seizer P. Lindemann S. Gawaz M. Platelet lipoprotein interplay: trigger of foam cell formation and driver of atherosclerosis.Cardiovasc Res. 2008; 78: 8-17Crossref PubMed Scopus (93) Google Scholar The development of atherosclerotic plaque involves endothelial activation, hypertrophy and hyperplasia of SMCs, monocyte migration, macrophage activation, uptake of lipids by activated cells, accumulation of fat, and formation of foam cells (Figure 2). Rapamycin inhibits monocyte/macrophage migration and their accumulation in carotid lesions of cholesterol-fed rabbits.18Baetta R. Granata A. Canavesi M. Ferri N. Arnaboldi L. Bellosta S. Pfister P. Corsini A. Everolimus inhibits monocyte/macrophage migration in vitro and their accumulation in carotid lesions of cholesterol-fed rabbits.J Pharmacol Exp Ther. 2009; 328: 419-425Crossref PubMed Scopus (52) Google Scholar Hyperfunctional adipocytes and hepatocytes increase levels of lipoproteins, such as low-density lipoprotein and procoagulation and pro-inflammation factors. Hyperfunction of bone marrow–derived cells, such as monocytes, lymphocytes, and platelets, contributes to atherosclerosis and thrombosis. Increased propensities to thrombosis, hyperlipidemia, pro-inflammation, and high blood pressure, which are systemic manifestations of cellular hyperfunctions, all contribute to atherosclerosis. In animal models, rapamycin slows the progression of atherosclerosis in apolipoprotein E–deficient mice that have elevated levels of cholesterol.19Pakala R. Stabile E. Jang G.J. Clavijo L. Waksman R. 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Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: a randomized clinical trial.Circulation. 2004; 110: 2694-2700Crossref PubMed Scopus (386) Google Scholar In patients with coronary atherosclerosis, oral rapamycin prevents restenosis after implantation of a metal stent.22Rodriguez A.E. Granada J.F. Rodriguez-Alemparte M. Vigo C.F. Delgado J. Fernandez-Pereira C. Pocovi A. Rodriguez-Granillo A.M. Schulz D. Raizner A.E. Palacios I. O'Neill W. Kaluza G.L. Stone G. ORAR II InvestigatorsOral rapamycin after coronary bare-metal stent implantation to prevent restenosis: the Prospective, Randomized Oral Rapamycin in Argentina (ORAR II) Study.J Am Coll Cardiol. 2006; 47: 1522-1529Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar Despite the common misconception that rapamycin may cause cancer, it has been known for a decade that rapamycin prevents cancers in renal transplant recipients.23Mathew T. Kreis H. 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Friend P. Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies.Clin Transplant. 2004; 18: 446-449Crossref PubMed Scopus (268) Google Scholar In addition, rapamycin prevented tumors and cured pre-existing tumors.26Stallone G. Schena A. Infante B. Di Paolo S. Loverre A. Maggio G. Ranieri E. Gesualdo L. Schena F.P. Grandaliano G. Sirolimus for Kaposi's sarcoma in renal-transplant recipients.N Engl J Med. 2005; 352: 1317-1323Crossref PubMed Scopus (821) Google Scholar For example, kidney transplant recipients who had biopsy-proved Kaposi's sarcoma were switched to rapamycin therapy. Three months after the initiation of rapamycin therapy, all cutaneous Kaposi's sarcoma lesions had disappeared in all 15 patients.26Stallone G. Schena A. Infante B. Di Paolo S. Loverre A. Maggio G. Ranieri E. Gesualdo L. Schena F.P. Grandaliano G. Sirolimus for Kaposi's sarcoma in renal-transplant recipients.N Engl J Med. 2005; 352: 1317-1323Crossref PubMed Scopus (821) Google Scholar Rapamycin is also extremely effective in the prevention of cancer in animal models.27Granville C.A. Warfel N. Tsurutani J. Hollander M.C. Robertson M. Fox S.D. Veenstra T.D. Issaq H.J. Linnoila R.I. Dennis P.A. Identification of a highly effective rapamycin schedule that markedly reduces the size, multiplicity, and phenotypic progression of tobacco carcinogen-induced murine lung tumors.Clin Cancer Res. 2007; 13: 2281-2289Crossref PubMed Scopus (82) Google Scholar The cancer preventive effects of rapamycin may be the result of its anti-aging effect.28Blagosklonny M.V. Prevention of cancer by inhibiting aging.Cancer Biol Ther. 2008; 7: 1520-1524Crossref PubMed Scopus (98) Google Scholar In fact, calorie restriction (CR) that decelerates aging delays cancer. CR may slow aging by inhibiting mTOR.29Blagosklonny M.V. 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Caloric restriction in humans.Exp Gerontol. 2007; 42: 709-712Crossref PubMed Scopus (248) Google Scholar CR delays the onset of age-associated pathological conditions in primates. Specifically, CR reduces the incidence of diabetes, cancer, cardiovascular disease, and brain atrophy.53Colman R.J. Anderson R.M. Johnson S.C. Kastman E.K. Kosmatka K.J. Beasley T.M. Allison D.B. Cruzen C. Simmons H.A. Kemnitz J.W. Weindruch R. Caloric restriction delays disease onset and mortality in rhesus monkeys.Science. 2009; 325: 201-204Crossref PubMed Scopus (1726) Google Scholar Furthermore, CR slows aging and delays age-related diseases in nonobese humans.52Holloszy J.O. Fontana L. Caloric restriction in humans.Exp Gerontol. 2007; 42: 709-712Crossref PubMed Scopus (248) Google Scholar, 54Fontana L. Meyer T.E. Klein S. Holloszy J.O. 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But, it will be useful to prevent and decrease atherosclerosis, osteoporosis, and neurodegeneration, which eventually lead to either a myocardial infarction or a broken hip. Anti-aging therapy will be most useful to prevent diseases or stop their progression, rather than to treat short-term complications.