The acceleration of aging and Alzheimer’s disease through the biological mechanisms behind obesity and type II diabetes


The incidence of diabetes is predicted to increase to 21% by 2050. Currently, one third of US adults are obese and over 11% of these individuals have diabetes. Due to the growing need for therapeutic intervention to control and/or stabilize this increase in the incidence of diabetes in Western communities, gaining a comprehensive understanding of the association between obesity and Type 2 diabetes has become increasingly important to diabetes research. The increased cell senescence associated with diabetes has been associated with the limited ability of cells to divide, with indication of telomere shortening and genomic instability of the cells. Obese individuals have shorter telomeres suggesting an inverse relationship between adiposity and telomere length. The implication that Type 2 diabetes has on biological aging is of particular interest since telomere shortening in obesity and diabetes has been associated with an early risk for dementia and even progression to Alzheimer’s disease (AD). Lifestyle, nutrition and longevity are closely related and cellular senescence has been associated with telomere shortening and connected to longevity. Diet, cholesterol lowering drugs and exercise that control food intake and glucose tolerance in aging and diabetic individuals, via connections between liver circadian clocks and the suprachiasmatic nucleus in the brain, also have been shown to alter telomere lengths. Lifestyle interventions, such as diets low in fat and exercise, target the rise in obesity and associated telomere shortening by delaying or preventing the onset of Type 2 diabetes. The implementation of these anti-aging therapies early in life may prevent calorie overload and activation of calorie sensitive genes such as Sirtuin 1 (Sirt1). This may maintain telomere length and the control of obesity, which is linked to cardiovascular disease, diabetes and accelerates aging and AD.

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Martins, I. , Lim, W. , Wilson, A. , Laws, S. and Martins, R. (2013) The acceleration of aging and Alzheimer’s disease through the biological mechanisms behind obesity and type II diabetes. Health, 5, 913-920. doi: 10.4236/health.2013.55121.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Wells, J.C. (2006) The evolution of human fatness and susceptibility to obesity: An ethological approach. Biological Reviews of the Cambridge Philosophical Society, 81, 183-205. doi:10.1017/S1464793105006974
[2] O’Rahilly, S., et al. (2003) Minireview: Human obesitylessons from monogenic disorders. Endocrinology, 144, 3757-3764. doi:10.1210/en.2003-0373
[3] Testa, R. and Ceriello, A. (2007) Pathogenetic loop between diabetes and cell senescence. Diabetes Care, 30, 2974-2975. doi:10.2337/dc07-1534
[4] Eckel, R.H., et al. (2011) Obesity and type 2 diabetes: What can be unified and what needs to be individualized? Diabetes Care, 34, 1424-1430. doi:10.2337/dc11-0447
[5] Steinberger, J. and Daniels, S.R. (2003) Obesity, insulin resistance, diabetes, and cardiovascular risk in children: An American Heart Association scientific statement from the atherosclerosis, hypertension, and obesity in the Young Committee (council on cardiovascular disease in the young) and the Diabetes Committee (council on nutrition, physical activity, and metabolism). Circulation, 107, 1448-1453. doi:10.1161/01.CIR.0000060923.07573.F2
[6] Lee, M., et al. (2011) Inverse association between adiposity and telomere length: The Fels Longitudinal Study. American Journal of Human Biology, 23, 100-106. doi:10.1002/ajhb.21109
[7] Khalaf, D., Ye, L. and Shil, A.B. (2012) Telomere length and high-density lipoprotein cholesterol. Journal of the American Geriatrics Society, 60, 599. doi:10.1111/j.1532-5415.2011.03856.x
[8] Hsu, C.P., et al. (2008) Sirt1 protects the heart from aging and stress. The Journal of Biological Chemistry, 389, 221-231. doi:10.1515/BC.2008.032
[9] Borradaile, N.M. and Pickering, J.G. (2009) NAD(+), sirtuins, and cardiovascular disease. Current Pharmaceutical Design, 15, 110-117. doi:10.2174/138161209787185742
[10] Stein, S. and Matter, C.M. (2011) Protective roles of SIRT1 in atherosclerosis. Cell Cycle, 10, 640-647. doi:10.4161/cc.10.4.14863
[11] Shi, Y., Camici, G.G. and Luscher, T.F. (2010) Cardiovascular determinants of life span. Pflügers Archiv, 459, 315-324. doi:10.1007/s00424-009-0727-2
[12] Purushotham, A., et al. (2009) Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metabolism, 9, 327-338. doi:10.1016/j.cmet.2009.02.006
[13] Elliott, P.J. and Jirousek, M. (2008) Sirtuins: Novel targets for metabolic disease. Current Opinion in Investigational Drugs, 9, 371-378.
[14] Colak, Y., et al. (2011) SIRT1 as a potential therapeutic target for treatment of nonalcoholic fatty liver disease. Medical Science Monitor, 17, HY5-HY9. doi:10.12659/MSM.881749
[15] Zhang, Z., et al. (2010) Roles of SIRT1 in the acute and restorative phases following induction of inflammation. The Journal of Biological Chemistry, 285, 41391-41401. doi:10.1074/jbc.M110.174482
[16] Yoshizaki, T., et al. (2009) SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes. Molecular and Cellular Biology, 29, 1363-1374. doi:10.1128/MCB.00705-08
[17] Sasaki, T. and Kitamura, T. (2010) Roles of FoxO1 and Sirt1 in the central regulation of food intake. Endocrine Journal, 57, 939-946. doi:10.1507/endocrj.K10E-320
[18] Michan, S., et al. (2010) SIRT1 is essential for normal cognitive function and synaptic plasticity. The Journal of Neuroscience, 30, 9695-9707. doi:10.1523/JNEUROSCI.0027-10.2010
[19] Gao, J., et al. (2010) A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature, 466, 11051109. doi:10.1038/nature09271
[20] Guarente, L. (2008) Mitochondria—A nexus for aging, calorie restriction, and sirtuins? Cell, 132, 171-176. doi:10.1016/j.cell.2008.01.007
[21] Libert, S., Cohen, D. and Guarente, L. (2008) Neurogenesis directed by Sirt1. Nature Cell Biology, 10, 373-374. doi:10.1038/ncb0408-373
[22] Silva, J.P. and Wahlestedt, C. (2010) Role of Sirtuin 1 in metabolic regulation. Drug Discovery Today, 15, 781-791. doi:10.1016/j.drudis.2010.07.001
[23] Takata, Y., et al. (2012) Association between ApoE phenotypes and telomere erosion in Alzheimer’s disease. Journals of Gerontology. Series A: Biological Sciences and Medical Sciences, 67, 330-335. doi:10.1093/gerona/glr185
[24] Moghekar, A. and O’Brien, R.J. (2012) Con: Alzheimer’s disease and circadian dysfunction: Chicken or egg? Alzheimer’s Research & Therapy, 4, 26. doi:10.1186/alzrt129
[25] Wang, J., et al. (2010) The role of Sirt1: At the crossroad between promotion of longevity and protection against Alzheimer’s disease neuropathology. Biochimica et Biophysica Acta, 1804, 1690-1694. doi:10.1016/j.bbapap.2009.11.015
[26] Bonda, D.J., et al. (2011) The sirtuin pathway in ageing and Alzheimer disease: Mechanistic and therapeutic considerations. The Lancet Neurology, 10, 275-279. doi:10.1016/S1474-4422(11)70013-8
[27] Galimberti, D. and Scarpini, E. (2011) Inflammation and oxidative damage in Alzheimer’s disease: Friend or foe? Frontiers in Bioscience (Scholar Edition), 3, 252-266. doi:10.2741/s149
[28] Fresno, M., Alvarez, R. and Cuesta, N. (2011) Toll-like receptors, inflammation, metabolism and obesity. Archives of Physiology and Biochemistry, 117, 151-164. doi:10.3109/13813455.2011.562514
[29] Ikeoka, D., Mader, J.K. and Pieber, T.R. (2010) Adipose tissue, inflammation and cardiovascular disease. Revista da Associação Médica Brasileira, 56, 116-121. doi:10.1590/S0104-42302010000100026
[30] Maccioni, R.B., et al. (2009) The role of neuroimmunomodulation in Alzheimer’s disease. Annals of the New York Academy of Sciences, 1153, 240-246. doi:10.1111/j.1749-6632.2008.03972.x
[31] Arosio, B., et al. (2004) Interleukin-10 and interleukin-6 gene polymorphisms as risk factors for Alzheimer’s disease. Neurobiology of Aging, 25, 1009-1015. doi:10.1016/j.neurobiolaging.2003.10.009
[32] Godbout, J.P. and Johnson, R.W. (2004) Interleukin-6 in the aging brain. Journal of Neuroimmunology, 147, 141- 144. doi:10.1016/j.jneuroim.2003.10.031
[33] Scheff, J.D., et al. (2010) Modeling the influence of circadian rhythms on the acute inflammatory response. Journal of Theoretical Biology, 264, 1068-1076. doi:10.1016/j.jtbi.2010.03.026
[34] Shammas, M.A. (2011) Telomeres, lifestyle, cancer, and aging. Current Opinion in Clinical Nutrition & Metabolic Care, 14, 28-34. doi:10.1097/MCO.0b013e32834121b1
[35] Jennings, B.J., Ozanne, S.E. and Hales, C.N. (2000) Nutrition, oxidative damage, telomere shortening, and cellular senescence: individual or connected agents of aging? Molecular Genetics and Metabolism, 71, 32-42. doi:10.1006/mgme.2000.3077
[36] Farzaneh-Far, R., et al. (2010)Telomere length trajectory and its determinants in persons with coronary artery disease: Longitudinal findings from the heart and soul study. PLoS One, 5, e8612. doi:10.1371/journal.pone.0008612
[37] Zannolli, R., et al. (2008) Telomere length and obesity. Acta Paediatrica, 97, 952-954. doi:10.1111/j.1651-2227.2008.00783.x
[38] Ly, H. (2009) Genetic and environmental factors influencing human diseases with telomere dysfunction. International Journal of Clinical and Experimental Medicine, 2, 114-130.
[39] Palacios, J.A., et al. (2010) SIRT1 contributes to telomere maintenance and augments global homologous recombination. The Journal of Cell Biology, 191, 1299-1313. doi:10.1083/jcb.201005160
[40] Kagawa, Y. (2012) From clock genes to telomeres in the regulation of the healthspan. Nutrition Reviews, 70, 459- 471. doi:10.1111/j.1753-4887.2012.00504.x
[41] Sung, Y.H., et al. (2005) The pleiotropy of telomerase against cell death. Molecules and Cells, 19, 303-309.
[42] Chan, S.W. and Blackburn, E.H. (2002) New ways not to make ends meet: Telomerase, DNA damage proteins and heterochromatin. Oncogene, 21, 553-563. doi:10.1038/sj.onc.1205082
[43] Saretzki, G. (2009) Telomerase, mitochondria and oxidative stress. Experimental Gerontology, 44, 485-492. doi:10.1016/j.exger.2009.05.004
[44] Smith, L.L., Coller, H.A. and Roberts, J.M. (2003) Telomerase modulates expression of growth-controlling genes and enhances cell proliferation. Nature cell biology, 5, 474-479.
[45] Jiang, H., Ju, Z. and Rudolph, K.L. (2007) Telomere shortening and ageing. Zeitschrift für Gerontologie und Geriatrie, 40, 314-324. doi:10.1007/s00391-007-0480-0
[46] Grodstein, F., et al. (2008) Shorter telomeres may mark early risk of dementia: Preliminary analysis of 62 participants from the nurses’ health study. PLoS One, 3, e1590.
[47] Frojdo, S., et al. (2011) Phosphoinositide 3-kinase as a novel functional target for the regulation of the insulin signaling pathway by SIRT1. Molecular and Cellular Endocrinology, 335, 166-176. doi:10.1016/j.mce.2011.01.008
[48] Zhang, J. (2006) Resveratrol inhibits insulin responses in a SIRT1-independent pathway. Biochemical Journal, 397, 519-527.doi:10.1042/BJ20050977
[49] Qin, W., et al. (2006) Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. The Journal of Biological Chemistry, 281, 21745-21754. doi:10.1074/jbc.M602909200
[50] Sonneborn, J.J. (2012) Alternative strategy for Alzheimer’s disease: Stress response triggers. International Journal of Alzheimer’s Disease, 2012, Article ID: 684283.
[51] Franco, S., et al. (2006) Telomeres and telomerase in Alzheimer’s disease: Epiphenomena or a new focus for therapeutic strategy? Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 2, 164-168. doi:10.1016/j.jalz.2006.03.001
[52] Donmez, G., et al. (2010) SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10. Cell, 142, 320-332. doi:10.1016/j.cell.2010.06.020
[53] Mantel, C. and Broxmeyer, H.E. (2008) Sirtuin 1, stem cells, aging, and stem cell aging. Current Opinion in Hematology, 15, 326-331. doi:10.1097/MOH.0b013e3283043819
[54] Roglic, G., et al. (2005) The burden of mortality attributeable to diabetes: Realistic estimates for the year 2000. Diabetes Care, 28, 2130-2135. doi:10.2337/diacare.28.9.2130
[55] Colagiuri, S., et al. (2005) There really is an epidemic of type 2 diabetes. Diabetologia, 48, 1459-1463. doi:10.1007/s00125-005-1843-y
[56] Pavanello, S., et al. (2011) Shortened telomeres in individuals with abuse in alcohol consumption. International Journal of Cancer, 129, 983-992. doi:10.1002/ijc.25999
[57] Strandberg, T., et al. (2012) Association between alcohol consumption in healthy midlife and telomere length in older men. The Helsinki businessmen study. European Journal of Epidemiology, 27, 815-822. doi:10.1007/s10654-012-9728-0
[58] Pfluger, P.T., et al. (2008) SIRT1 protects against high-fat diet-induced metabolic damage. Proceedings of the National Academy of Sciences of the United States of America, 105, 9793-9798. doi:10.1073/pnas.0802917105
[59] Deng, X.Q., Chen, L.L. and Li, N.X. (2007) The expression of SIRT1 in nonalcoholic fatty liver disease induced by high-fat diet in rats. Liver International, 27, 708-715. doi:10.1111/j.1478-3231.2007.01497.x
[60] Mulder, H. (2010) Is shortening of telomeres the missing link between aging and the type 2 diabetes epidemic? Aging (Albany NY), 2, 634-636.
[61] Cunningham, S.A., et al. (2011) Decreases in diabetes-free life expectancy in the US and the role of obesity. Diabetes Care, 34, 2225-2230. doi:10.2337/dc11-0462
[62] Farrell, G.C., et al. (2012) NASH is an inflammatory disorder: Pathogenic, prognostic and therapeutic implications. Gut Liver, 6, 149-171. doi:10.5009/gnl.2012.6.2.149
[63] Katic, M. and Kahn, C.R. (2005) The role of insulin and IGF-1 signaling in longevity. Cellular and Molecular Life Sciences, 62, 320-343. doi:10.1007/s00018-004-4297-y
[64] Aravinthan, A., et al. (2012) Hepatocyte senescence predicts progression in non-alcohol-related fatty liver disease. Journal of Hepatology, 58, 549-556.
[65] Hewitt, G., et al. (2012) Telomeres are favoured targets of a persistent DNA damage response in ageing and stressinduced senescence. Nature Communications, 3, 708. doi:10.1038/ncomms1708
[66] Monickaraj, F., et al. (2012) Accelerated aging as evidenced by increased telomere shortening and mitochondrial DNA depletion in patients with type 2 diabetes. Molecular and Cellular Biochemistry, 365, 343-350. doi:10.1007/s11010-012-1276-0
[67] Nakajima, T., et al. (2010) Nuclear size measurement is a simple method for the assessment of hepatocellular aging in non-alcoholic fatty liver disease: Comparison with telomere-specific quantitative FISH and p21 immunohistochemistry. Pathology International, 60, 175-183. doi:10.1111/j.1440-1827.2009.02504.x
[68] Nakajima, T., et al. (2006) Premature telomere shortening and impaired regenerative response in hepatocytes of individuals with NAFLD. Liver International, 26, 23-31. doi:10.1111/j.1478-3231.2005.01178.x
[69] Weldemichael, D.A. and Grossberg, G.T. (2010) Circadian rhythm disturbances in patients with Alzheimer’s disease: A review. International Journal of Alzheimer’s Disease, 2010, Article ID: 716453.
[70] Okamura, H. (2007) Suprachiasmatic nucleus clock time in the mammalian circadian system. Cold Spring Harbor Symposia on Quantitative Biology, 72, 551-556. doi:10.1101/sqb.2007.72.033
[71] Coomans, C.P., et al. (2012) The suprachiasmatic nucleus controls circadian energy metabolism and hepatic insulin sensitivity. Diabetes, 62, 1102-1108.
[72] Garaulet, M. and Madrid, J.A. (2010) Chronobiological aspects of nutrition, metabolic syndrome and obesity. Advanced Drug Delivery Reviews, 62, 967-978. doi:10.1016/j.addr.2010.05.005
[73] Baitsch, D., et al. (2011) Apolipoprotein E induces antiinflammatory phenotype in macrophages. Arteriosclerosis, Thrombosis, and Vascular Biology, 31, 1160-1168. doi:10.1161/ATVBAHA.111.222745
[74] Ali, K., et al. (2005) Apolipoprotein E suppresses the type I inflammatory response in vivo. Circulation Research, 97, 922-927. doi:10.1161/01.RES.0000187467.67684.43
[75] Esteve, E., Ricart, W. and Fernandez-Real, J.M. (2005) Dyslipidemia and inflammation: An evolutionary conserved mechanism. Clinical Nutrition, 24, 16-31. doi:10.1016/j.clnu.2004.08.004
[76] Romon, M., et al. (1997) Circadian variation of postprandial lipemia. The American Journal of Clinical Nutrition, 65, 934-940.
[77] Mondola, P., et al. (1995) Circadian rhythms of lipid and apolipoprotein pattern in adult fasted rats. Physiology & Behavior, 58, 175-180. doi:10.1016/0031-9384(95)00016-C
[78] Kang, J.E., et al. (2009) Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science, 326, 1005-1007. doi:10.1126/science.1180962
[79] Bhagavati, S. (2008) Marked hyperphagia associated with total loss of satiety in Alzheimer’s disease. The Journal of Neuropsychiatry and Clinical Neurosciences, 20, 248249.
[80] Martins, I.J., et al. (1994) Lipid and apolipoprotein B48 transport in mesenteric lymph and the effect of hyperphagia on the clearance of chylomicron-like emulsions in insulin-deficient rats. Diabetologia, 37, 238-246. doi:10.1007/BF00398049
[81] Tsang, S.W., et al. (2010) A serotoninergic basis for hyperphagic eating changes in Alzheimer’s disease. Journal of the Neurological Sciences, 288, 151-155. doi:10.1016/j.jns.2009.08.066
[82] Olivieri, F., et al. (2012) Telomere/telomerase system: A new target of statins pleiotropic effect? Current Vascular Pharmacology, 10, 216-224. doi:10.2174/157016112799305076
[83] Brouilette, S.W., et al. (2007) Telomere length, risk of coronary heart disease, and statin treatment in the west of Scotland primary prevention study: A nested case-control study. The Lancet, 369, 107-114. doi:10.1016/S0140-6736(07)60071-3
[84] Bernardes de Jesus, B., et al. (2011) The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence. Aging Cell, 10, 604-621. doi:10.1111/j.1474-9726.2011.00700.x

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