In this article we review the association of three principal factors of the metabolic syndrome— insulin resistance, hypertension, and increased levels of inflammation factors—with several chronic, nonatherosclerotic conditions associated with aging—frailty, cognitive decline, impaired cardiovascular autonomic control, and possibly osteoporosis. We hypothesize that the metabolic syndrome is associated with “accelerated” aging.
Get full access to this article
View all access options for this article.
References
1.
MeigsJB. Invited commentary: Insulin resistance syndrome? Syndrome X? Multiple metabolic syndrome? A syndrome at all? Factor analysis reveals patterns in the fabric of correlated metabolic risk factors. Am J Epidemiol, 2000; 152:908–911.
2.
SakkinenPA, WahlP, CushmanM, LewisMR, TracyRP. Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome. Am J Epidemiol, 2000; 152:897–907.
3.
HaffnerSM. The metabolic syndrome: Inflammation, diabetes mellitus, and cardiovascular disease. Am J Cardiol, 2006; 97:3A–11A.
4.
McNeillAM, KatzR, GirmanCJ, RosamondWD, WagenknechtLE, BarzilayJI, TracyRP, SavagePJ, JacksonSA. Metabolic syndrome and cardiovascular disease in the elderly. The Cardiovascular Health Study. J Am Geriatr Soc, 2006; 54:1317–1324.
5.
GinsburgHN, MacCallumPR. The obesity, metabolic syndrome, and type 2 diabetes mellitus pandemic: Part 1. Increased cardiovascular disease risk and the importance of atherogenic dyslipidemia in persons with the metabolic syndrome and type 2 diabetes mellitus. J Cardiometab Syndr, 2009; 4:113–119.
6.
FriedLP, XueQL, CappolaAR, FerrucciL, ChavesP, VaradhanR, GuralnikJM, LengSX, SembaRD, WalstonJD, BlaumCS, Bandeen-RocheK. Nonlinear multisystem physiological dysregulation associated with frailty in older women: Implications for etiology and treatment. J Gerontol A Biol Sci Med Sci, 2009; 64:1049–1057.
7.
Bortz WMII. A conceptual framework for frailty: A review. J Gerontol A Biol Sci Med Sci, 2002; 57:M283–M288.
8.
WalstonJ, McBurnieMA, NewmanA, TracyRP, KopWJ, HirschCH, GottdienerJ, FriedLP. Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities. Results from the Cardiovascular Health Study. Arch Intern Med, 2002; 162:2333–2341.
9.
BarzilayJI, BlaumC, MooreT, XueQL, HirschCH, WalstonJD, FriedLP. Insulin resistance and inflammation as precursors of frailty: The Cardiovascular Health Study. Arch Intern Med, 2007; 167:635–641.
10.
DegensH. The role of systemic inflammation in age-related muscle weakness and wasting. Scand J Med Sci Sports, 2010; 20:28–38.
11.
GelfandRA, BarrettEJ. Effect of physiologic hyperinsulinemia on skeletal muscle protein synthesis and breakdown in man. J Clin Invest, 1987; 80:1–6.
12.
AbbatecolaAM, FerrucciL, CedaG, RussoCR, LauretaniF, BandinelliS, BarbieriM, ValentiG, PaolissoG. Insulin resistance and muscle strength in older persons. J Gerontol A Biol Sci Med Sci, 2005; 60:1278–1282.
13.
BarzilayJI, CotsonisGA, WalstonJ, SchwartzAV, SatterfieldS, MiljkovicI, HarrisT. Insulin resistance is associated with decreased quadriceps muscle strength in non-diabetic adults, age >70 years. Diabetes Care, 2009; 32:736–738.
14.
Diabetes Prevention Program ResearchGroup, CrandallJ, SchadeD, MaY, FujimotoWY, Barrett-ConnorE, FowlerS, Dagogo-JackS, AndresR. The influence of age on the effects of lifestyle modification and metformin in prevention of diabetes. J Gerontol A Biol Sci Med Sci, 2006; 61:1075–1081.
15.
LanzaIR, ShortDK, ShortKR, RakhavakaimalS, BasuR, JoynerMJ, McConnellJP, NairKS. Endurance training as a countermeasure for aging. Diabetes, 2008; 57:2933–2942.
16.
CukiermanT, GersteinHC, WilliamsonJD. Cognitive decline and dementia in diabetes–systematic overview of prospective observational studies. Diabetologia, 2005; 48:2460–2469.
17.
EuserSM, SattarN, WittemanJC, BollenEL, SijbrandsEJ, HofmanA, PerryIJ, BretelerMM, WestendorpRG. PROSPER and Rotterdam Study. A prospective analysis of elevated fasting glucose levels and cognitive function in older people: Results from PROSPER and the Rotterdam Study. Diabetes, 2010; 59:1601–1607.
18.
WilliamsonJD, MillerME, BryanRN, LazarRM, CokerLH, JohnsonJ, CukiermanT, HorowitzKR, MurrayA, LaunerLJ. ACCORD Study Group. The action to control cardiovascular risk in diabetes memory in diabetes study (ACCORD-MIND): rationale, design, and methods. Am J Cardiol, 2007; 99:S112–S122.
19.
FrisardiV, SolfrizziV, SeripaD, CapursoC, SantamatoA, SancarloD, VendemialeG, PilottoA, PanzaF. Metabolic-cognitive syndrome: A cross-talk between metabolic syndrome and Alzheimer's disease. Ageing Res Rev, 2010; 9:399–417.
20.
RuisC, BiesselsGJ, GorterKJ, van den DonkM, KappelleLJ, RuttenGE. Cognition in the early stage of type 2 diabetes. Diabetes Care, 2009; 32:1261–1265.
21.
DikMG, JonkerC, ComijsHC, DeegDJ, KokA, YaffeK, PenninxBW. Contribution of metabolic syndrome components to cognition in older individuals. Diabetes Care, 2007; 30:2655–2660.
22.
YaffeK, KanayaA, LindquistK, SimonsickEM, HarrisT, ShorrRI, TylavskyFA, NewmanAB. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA, 2004; 292:2237–2242.
23.
KomulainenP, LakkaTA, KivipeltoM, HassinenM, HelkalaEL, HaapalaI, NissinenA, RauramaaR. Metabolic syndrome and cognitive function: A population-based follow-up study in elderly women. Dement Geriatr Cogn Disord, 2007; 23:29–34.
24.
RaffaitinC, GinH, EmpanaJP, HelmerC, BerrC, TzourioC, PortetF, DartiguesJF, AlpérovitchA, Barberger-GateauP. Metabolic syndrome and risk for incident Alzheimer's disease or vascular dementia: The Three-City Study. Diabetes Care, 2009; 32:169–174.
25.
VanhanenM, KoivistoK, MoilanenL, HelkalaEL, HänninenT, SoininenH, KervinenK, KesäniemiYA, LaaksoM, KuusistoJ. Association of metabolic syndrome with Alzheimer disease: A population-based study. Neurology, 2006; 67:843–847.
26.
LaudisioA, MarzettiE, PaganoF, CocchiA, FranceschiC, BernabeiR, ZuccalàG. Association of metabolic syndrome with cognitive function: The role of sex and age. Clin Nutr, 2008; 27:747–754.
27.
MullerM, TangMX, SchupfN, ManlyJJ, MayeuxR, LuchsingerJA. Metabolic syndrome and dementia risk in a multiethnic elderly cohort. Dement Geriatr Cogn Disord, 2007; 24:185–192.
28.
FortiP, PisacaneN, RiettiE, LucicesareA, OlivelliV, MarianiE, MecocciP, RavagliaG. Metabolic syndrome and risk of dementia in older adults. J Am Geriatr Soc, 2010; 58:487–492.
29.
CavalieriM, RopeleS, PetrovicK, Pluta-FuerstA, HomayoonN, EnzingerC, GrazerA, KatschnigP, SchwingenschuhP, BergholdA, SchmidtR. Metabolic syndrome, brain magnetic resonance imaging, and cognition. Diabetes Care, 2010; 33:2489–2495.
30.
DikMG, JonkerC, ComijsHC, DeegDJ, KokA, YaffeK, PenninxBW. Contribution of metabolic syndrome components to cognition in older individuals. Diabetes Care, 2007; 30:2655–2660.
31.
RobertsRO, GedaYE, KnopmanDS, ChaRH, BoeveBF, IvnikRJ, PankratzVS, TangalosEG, PetersenRC. Metabolic syndrome, inflammation, and non-amnestic mild cognitive impairment in older persons: A population-based study. Alzheimer Dis Assoc Disord, 2010; 24:11–18.
32.
SolfrizziV, ScafatoE, CapursoC, D'IntronoA, ColaciccoAM, FrisardiV, VendemialeG, BaldereschiM, CrepaldiG, Di CarloA, GalluzzoL, GandinC, InzitariD, MaggiS, CapursoA, PanzaF. Italian Longitudinal Study on Ageing Working Group. Metabolic syndrome and the risk of vascular dementia: The Italian Longitudinal Study on Ageing. J Neurol Neurosurg Psychiatry, 2010; 81:433–440.
33.
AbbatecolaAM, PaolissoG, LamponiM, BandinelliS, LauretaniF, LaunerL, FerrucciL. Insulin resistance and executive dysfunction in older persons. J Am Geriatr Soc, 2004; 52:1713–1718.
34.
van OijenM, OkerekeOI, KangJH, PollakMN, HuFB, HankinsonSE, GrodsteinF. Fasting insulin levels and cognitive decline in older women without diabetes. Neuroepidemiology, 2008; 30:174–179.
35.
SchuurM, HennemanP, van SwietenJC, ZillikensMC, de KoningI, JanssensAC, WittemanJC, AulchenkoYS, FrantsRR, OostraBA, van DijkKW, van DuijnCM. Insulin-resistance and metabolic syndrome are related to executive function in women in a large family-based study. Eur J Epidemiol, 2010; 25:561–568.
36.
RasgonNL, KennaHA, WroolieTE, KelleyR, SilvermanD, BrooksJ, WilliamsKE, PowersBN, HallmayerJ, ReissA. Insulin resistance and hippocampal volume in women at risk for Alzheimer's disease. Neurobiol Aging, 2009Dec24[Epub ahead of print].
37.
TournoyJ, LeeDM, PendletonN, O'NeillTW, O'ConnorDB, BartfaiG, CasaneuvaFF, FinnJD, FortiG, GiwercmanA, HanTS, HuhtaniemiIT, KulaK, LeanME, MoseleyCM, PunabM, SilmanAJ, VanderschuerenD, WuFC, BoonenS. EMAS Study Group. Association of cognitive performance with the metabolic syndrome and with glycaemia in middle-aged and older European men: The European Male Ageing Study. Diabetes Metab Res Rev, 2010; 26:668–676.
38.
LaunerLJ, MasakiK, PetrovitchH, FoleyD, HavlikRJ. The association between midlife blood pressure levels and late-life cognitive function. The Honolulu-Asia Aging Study. JAMA, 1995; 274:1846–1851.
MilionisHJ, FlorentinM, GiannopoulosS. Metabolic syndrome and Alzheimer's disease: A link to a vascular hypothesis?CNS Spectr, 2008; 13:606–613.
41.
LopezOL, JagustWJ, DulbergC, BeckerJT, DeKoskyST, FitzpatrickA, BreitnerJ, LyketsosC, JonesB, KawasC, CarlsonM, KullerLH. Risk factors for mild cognitive impairment in the Cardiovascular Health Study Cognition Study: Part 2. Arch Neurol, 2003; 60:1394–1399.
42.
ReitzC, TangM-X, ManlyJ, MayeuxJ, LuchsingerJA. Hypertension and the risk of mild cognitive impairment. Arch Neurol, 2007; 64:1734–1740.
43.
BarzilayJI, PetersonD, CushmanM, HeckbertSR, CaoJJ, BlaumC, TracyRP, KleinR, HerringtonDM. The relationship of cardiovascular risk factors to microalbuminuria in older adults with or without diabetes mellitus or hypertension: The cardiovascular health study. Am J Kidney Dis, 2004; 44:25–34.
44.
FarkasE, LuitenPGM. Cerebral microvascular pathology in aging and Alzheimer's disease. Prog Neurobiol, 2001; 64:575–611.
45.
FiorettoP, SteffesMW, BrownDM, MauerSM. An overview of renal pathology in insulin-dependent diabetes mellitus in relationship to altered glomerular hemodynamics. Am J Kidney Dis, 1992; 20:549–558.
46.
BarzilayJI, FitzpatrickA, LuchsingerJ, YasarS, BernickC, JennyNS, KullerLH. Albuminuria and dementia in the elderly: A community study. Am J Kid Dis, 2008; 52:216–226.
47.
BarzilayJI, GaoP, O'DonnellM, MannJFE, AndersonC, FagardR, ProbstfieldJ, DagenaisGR, TeoK, YusufS. Albuminuria and decline in cognitive function: The ONTARGET / TRANSCEND Studies. Arch Intern Med, 2011; 171:142–150.
48.
GargAX, KiberdBA, ClarkWF, HaynesRB, ClaseCM. Albuminuria and renal insufficiency prevalence guides population screening: Results from NHANES III. Kidney Int, 2002; 61:2165–2175.
49.
ChenJ, MuntnerP, HammLL, JonesDW, BatumanV, FonsecaV, WheltonPK, HeJ. The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med, 2004; 140:167–174.
50.
BarzilayJI, PetersonD, CushmanM, HeckbertSR, CaoJJ, BlaumC, TracyRP, KleinR, HerringtonDM. The relationship of cardiovascular risk factors to microalbuminuria in older adults with or without diabetes mellitus or hypertension: The Cardiovascular Health Study. Am J Kid Dis, 2004; 44:25–34.
51.
MitchellGF. Effects of central arterial aging on the structure and function of the peripheral vaculature; implications for end-organ damage. J Appl Physiol, 2008; 105:1652–1660.
VallonV. The proximal tubule in the pathophysiology of the diabetic kidney. Am J Physiol Regul Integr Comp Physiol, 2011; 300:R1009–R1022.
54.
ParkK, YasudaN, ToyonagaS, YamadaSM, NakabayashiH, NakasatoM, NakagomiT, TsubosakiE, ShimizuK. Significant association between leukoaraiosis and metabolic syndrome in healthy subjects. Neurology, 2007; 69:974–978.
55.
HollingworthP, HaroldD, SimsRet al.Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nature Genet, 2011, 10.1038/ng.803
56.
KleigerRE, SteinPK, BiggerJT. Heart rate variability: measurement and clinical utility. Ann Noninvasive Electrocardiol, 2005; 10:1–14.
57.
SteinPK, BarzilayJI. Relationship of abnormal heart rate turbulence and elevated CRP to cardiac mortality in low, intermediate, and high-risk older adults. J Cardiovasc Electrophysiol, 2011; 22:122–127.
58.
DenysK, CankurtaranM, JanssensW, PetrovicM. Metabolic syndrome in the elderly: An overview of the evidence. Acta Clin Belg, 2009; 64:23–34.
59.
SteinPK, BarzilayJI, DomitrovichPP, ChavesPM, GottdienerJS, HeckbertSR, KronmalRA. The relationship of heart rate and heart rate variability to non-diabetic fasting glucose levels and the metabolic syndrome: The Cardiovascular Health Study. Diab Med, 2007; 24:855–863.
60.
SchroederEB, ChamblessLE, LiaoD, PrineasRJ, EvansGW, RosamondWD, HeissG. Diabetes, glucose, insulin, and heart rate variability: The Atherosclerosis Risk in Communities (ARIC) study. Diabetes Care, 2005; 28:668–674.
61.
SinghJP, LarsonMG, O'DonnellCJ, WilsonPF, TsujiH, Lloyd-JonesDM, LevyD. Association of hyperglycemia with reduced heart rate variability (The Framingham Heart Study)Am J Cardiol, 2000; 86:309–312.
62.
SteinPK, BarzilayJI, ChavesPHM, TraberJ, DomitrovichPP, HeckbertSR, GottdienerJS. Inflammation factors and insulin resistance are independently associated with increased heart rate and diminished heart rate variability in normoglycemic older individuals: The Cardiovascular Health Study. J Am Geriat Soc, 2008; 56:315–321.
63.
LiaoD, SloanRP, CascioWP, FolsomAR, LieseAD, EvansGW. Multiple metabolic syndrome is associated with lower heart rate variability. The Atherosclerosis Risk in Communities Study. Diabetes Care, 1998; 21:2116–2122.
64.
FestaA, D'AgostinoRJr, HalesCN, MykkänenL, HaffnerSM. Heart rate in relation to insulin sensitivity and insulin secretion in nondiabetic subjects. Diabetes Care, 2000; 23:624–628.
65.
PikkujämsäSM, HuikuriHV, AiraksinenKE, RantalaAO, KaumaH, LiljaM, SavolainenMJ, KesäniemiYA. Heart rate variability and baroreflex sensitivity in hypertensive subjects with and without metabolic features of insulin resistance syndrome. Am J Hypertens, 1998; 11:523–531.
66.
ScheerFA, HiltonMF, MantzorosCS, SheaSA. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci USA, 2009; 106:4453–4458.
67.
LumengJC, SomashekarD, AppuglieseD, KacirotiN, CorwynRF, BradleyRH. Shorter sleep duration is associated with increased risk for being overweight at ages 9 to 12 years. Pediatrics, 2007; 120:1020–1029.
68.
GreenCB, TakahashiJS, BassJ. The meter of metabolism. Cell, 2008; 134:728–742.
69.
MauryE, RamseyKM, BassJ. Circadian rhythms and metabolic syndrome. From experimental genetics to human disease. Circ Res, 2010; 106:447–462.
70.
GibsonEM, WilliamsWP, KriegsfeldLJ. Aging in the circadian system: Considerations for health, disease prevention, and longevity. Exp Gerontol, 2009; 44:51–56.
71.
CavadiniG, PetrzilkaS, KohlerP, JudC, ToblerI, BirchlerT, FontanaA. TNF-alpha suppresses the expression of clock genes by interfering with E-box-mediated transcription. Proc Natl Acad Sci USA, 2007; 104:12843–12848.
72.
VgontzasAN, ZoumakisE, LinHM, BixlerEO, TrakadaG, ChrousosGP. Marked decrease in sleepiness in patients with sleep apnea by etanercept, a tumor necrosis factor-alpha antagonist. J Clin Endocrinol Metab, 2004; 89:4409–4413.
73.
MaemuraK, de la MonteSM, ChinMT, LayneMD, HsiehCM, YetSF, PerrellaMA, LeeME. CLIF, a novel cycle-like factor, regulates the circadian oscillation of plasminogen activator inhibitor-1 gene expression. J Biol Chem, 2000; 275:36847–36851.
SteinPK, BarzilayJI. Abnormal heart rate turbulence predicts cardiac mortality in low, intermediate and high risk older adults. J Cardiovasc Electrophysiol, 2011; 22:122–127.
76.
KleigerRE, MillerJP, BiggerJT, MossAJ. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol, 1987; 59:256–262.
77.
KinjoM, SetoguchiS, SolomonDH. Bone mineral density in adults with the metabolic syndrome: Analysis of a population-based U.S. sample. J Clin Endocrinol Metab, 2007; 92:4161–4164.
78.
Von MuhlenD, SafiiS, JassalSK, SvartbergJ, Barrett-ConnorE. Associations between the metabolic syndrome and bone health in older men and women: The Rancho Bernardo Study. Osteoporos Int, 2007; 18:1337–1344.
79.
YaturuS, HumphreyS, LandryC, JainSK. Decreased bone mineral density in men with the metabolic syndrome alone and with type 2 diabetes. Med Sci Monitor, 2009; 15:CR5–CR9.
80.
AhmedLA, SchirmerH, BerntsenGK, Fonnebo, JoakimsenRM. Features of the metabolic syndrome and risk of non-vertebral fractures: The TromsØ Study. Osteoporos Int, 2006; 17:426–432.
81.
KimHY, ChoeJW, KimHK, BaeSJ, KimBJ, LeeSH, KohJM, HanKO, ParkHM, KimGS. Negative association between metabolic syndrome and bone mineral density in Koreans, especially men. Calcif Tisse Int, 2010; 86:350–358.
82.
TsengYH, HuangKC, LiuML, ShuWT, SheuWH. Association between metabolic syndrome (MS) and bone mineral loss: A cross-sectional study in Puli Township in Taiwan. Arch Gerontol Geriatr, 2009; 49,Suppl 2:S37–S40.
83.
KnowlerWC, Barrett-ConnorE, FowlerSE, HammanRF, LachinJM, WalkerEA, NathanDM. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med, 2002; 346:393–403.
84.
OeseburgH, de BoerRA, van GilstWH, van der HarstP. Telomere biology in healthy aging and disease. Pflugers Arch, 2010; 459:259–268.
85.
O'CallaghanNJ, CliftonPM, NoakesM, FenechM. Weight loss in obese men is associated with increased telomere length and decreased abasic sites in rectal mucosa. Rejuvenation Res, 2009; 12:169–176.
86.
GoldfineAB, FonsecaV, JablonskiKA, PyleL, StatenMA, ShoelsonSE. TINSAL-T2D (Targeting Inflammation Using Salsalate in Type 2 Diabetes) Study Team. The effects of salsalate on glycemic control in patients with type 2 diabetes: A randomized trial. Ann Intern Med, 2010; 152:346–357.
