dissecting the mechanisms underlying unusually...

Dissecting the Mechanisms UnderlyingUnusually Successful Human Health Spanand Life Span

Sofiya Milman1,2 and Nir Barzilai1,2,3

1Department of Medicine, Division of Endocrinology, Albert Einstein College of Medicine,New York, New York 10461

2Institute for Aging Research, Albert Einstein College of Medicine, New York, New York 104613Department of Genetics, Albert Einstein College of Medicine, Bronx, New York 10461

Correspondence: [email protected]

Humans age at different rates and families with exceptional survival provide the opportunityto understand why some people age slower than others. Unique features exhibited by cen-tenarians include a family history of longevity, compression of morbidity with resultantextension of health span, and biomarkers such as low-circulating insulin-like growthfactor 1 (IGF-1) and elevated high-density lipoprotein (HDL) cholesterol levels. Given therarity of the centenarian phenotype, it has not been surprising that the use of discoverymethods that relied on common population single nucleotide polymorphisms (SNPs) tounlock the genetic determinants of exceptional longevity have not yielded significantresults. Conversely, gene sequencing has resulted in discoveries of functional gene variantsthat support several of the centenarian phenotypes. These discoveries have led to the strategicdevelopments of drugs that may delay aging and prolong health span.

THE RATIONALE FOR STUDYING HUMANEXCEPTIONAL LONGEVITY

The Unites States government annually pub-lishes a report on the rate of death from in-

dividual diseases, stratified by age groups.What’s striking about these reports is that therate of death increases logarithmically with ad-vancing age for all diseases associated with ag-ing, including heart disease, cancer, stroke, di-abetes mellitus type 2 (T2DM), and Alzheimer’sdisease (AD) (Fig. 1). This shows that aging is amajor risk factor that all of these age-related

diseases have in common. To put these statisticsin perspective, elevated low-density lipoprotein(LDL) cholesterol level, which is one of the bestknown and aggressively treated risk factors forheart disease, the most common cause of deathamong older adults, is associated with a three-fold increase in the risk for heart disease. How-ever, advancing the age from 30 years to 80 yearsraises the rate of death from each of the age-related diseases by as much as 100- to 1000-fold. If we accept the notion that aging is thecommon and major risk factor for all age-relat-ed diseases, then we conclude that unless aging

Editors: S. Jay Olshansky, George M. Martin, and James L. Kirkland

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itself is delayed our best attempts at preventingeach disease individually will result in exchang-ing one disease for another. The return for cur-ing individual diseases is small. For example,statistical models project that delaying cancerwould result in an increase of only 0.8% in thepopulation of older adults over a 50-year period,whereas delaying aging would lead to an increaseof �7% in the population, with most of theseindividuals being free of disability (Goldmanet al. 2013). Furthermore, this delay in agingwould yield �$7.1 trillion in social benefit tothe population (Goldman et al. 2013).

When thinking about aging, it is importantto recognize that chronological and biologicalage are not the same. It is well recognized by allthat some individuals appear younger thantheir chronological age, whereas others appearolder. This observation highlights an opportu-nity for scientific discovery that until recentlyhas been missed, that is, to try to understandthe biology of why some age faster while othersage slower. At one extreme of the spectrum ofthe rate of aging are rare segmental progeroidsyndromes that are thought to accelerate vari-ous aging phenotypes. The responsible genemutations have suggested genomic instabilityas an important mechanism of aging (Martin2005). More recently, scientists have becomeinterested in studying people with exceptionallongevity, which are located at the other end ofthe rate of aging spectrum, in an effort to dis-cover the genetic and biological determinantsof delayed aging.

Centenarians are a unique group of individ-uals that constitute an example of delayed aging.

This delay in aging can only be accomplished ifit results in the extension of disease-free survivaland, indeed, this appears to be the case in manycentenarians. Analyses from the New EnglandCentenarian Study (Andersen et al. 2012), theLong Life Family Study (LLFS) (Sebastiani etal. 2013), and the Longevity Genes Program(Ismail 2014) have provided evidence that in-dividuals with exceptional longevity manifestcompression of morbidity, meaning that theyspend a smaller percentage of their life beingill, and, as a result, their health span approx-imates their life span. These studies revealedsignificant delay in the ages of onset for mostage-related diseases among individuals with ex-ceptional longevity, including hypertension,cardiovascular disease (CVD), cancer, T2DM,stroke, osteoporosis, and AD. Thus, not onlydo centenarians live longer, they live healthier.Although a large proportion of centenariansdelay or escape from age-related diseases alto-gether (Evans et al. 2014), a number of individ-uals achieve exceptional longevity despite hav-ing developed one or several of these diseases(Andersen et al. 2012; Ailshire et al. 2015). Thissuggests that these people likely possess protec-tive factors that allow them to be resilient andsurvive despite health ailments.

The inherent differences between chrono-logical and biological age, and between the di-verse rates of aging, offer scientists opportuni-ties to study the variations in the biology andgenetics among these different groups. As ex-emplified in the literature, several mechanismshave already been identified that can delay agingin a variety of animal models. Investigating

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Figure 1. Rate of death per 100,000 people per year for age-related diseases, stratified by age groups (from Health,United States, 2014, www.cdc.gov/nchs/hus.htm).

S. Milman and N. Barzilai

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whether these same mechanisms apply to hu-mans with exceptional longevity serves to vali-date these discoveries as important for humanaging. Furthermore, studies are underway fordiscovery of age-delaying mechanisms that arespecific to humans by using centenarian popu-lations. The rationale for studying centenariansis that they are the “poster children” for what weare ultimately trying to achieve—extension ofhealth span and not merely life span.

THE EVIDENCE THAT LONGEVITY ISINHERITED

Demographers and epidemiologists have at-tributed �15%–30% of the variation in lifespan to heritable factors. Several studies havefound positive correlations between the lifespans of the parents and their biological chil-dren (Atzmon et al. 2004; Schoenmaker et al.2006; Westendorp et al. 2009). However, theadvances of modern medicine that include pre-ventive measures and treatments, have extend-ed the life spans of the newer generationsbeyond what would have been predicted basedon their inheritance. Thus, offspring whoseparents died from CVD resulting from heredi-tary hyperlipidemia, can now enjoy an exten-sion of their life span through treatment withcholesterol-lowering medications and inter-ventions such as coronary artery bypass graftsurgery or revascularization of coronary arter-ies with angioplasty. Despite these significantmedical advances, achievement of exceptionallongevity remains a rare occurrence. Yet, excep-tional longevity clusters in families point to astrong relationship between genetics and lon-gevity.

Data suggests that the offspring of parentswho achieved a life span of at least 70 years havea much greater probability of living longercompared with the offspring of parents withshorter life spans, with this association becom-ing stronger as the parental life span lengthens(Gavrilov et al. 2001). This relationship is evenmore pronounced in families with exceptionallongevity. Siblings of centenarians have beenshown to be �4–5 times more likely to achievelongevity, with male siblings being 17 times

more likely to become centenarians themselves(Perls et al. 1998, 2002). The parents of cente-narians were found to be seven times more likelyto have survived to age 90 and beyond, com-pared with parents of those with the usual lifespan (Atzmon et al. 2004). Even if genetics ac-count for smaller differences observed in therate of aging, identification of these genes isimportant for planning strategies that can delaythe aging process. Furthermore, because excep-tional longevity is heritable, studying the fami-lies of centenarians to identify genetic deter-minants of exceptional longevity offers greatpromise for discovery.

Familial longevity is likely mediated throughprotection from age-related diseases, which isinherited by the offspring from their parents.Centenarians and their offspring have a lowerprevalence and later age of onset of heart dis-ease, stroke, hypertension, T2DM, AD, and can-cer (Anderson et al. 1991; Atzmon et al. 2004;Adams et al. 2008; Lipton et al. 2010; Altmann-Schneider et al. 2012). This heritable protectionfrom disease has also been shown in severallarge studies. A prospective population-basedstudy found that the incidence of AD was 43%lower in offspring of parents with exceptionallongevity compared with offspring of parentswith more usual life spans over a 23-year fol-low-up (Lipton et al. 2010). A similar associa-tion was also found in a study conducted in apopulation whose parents achieved more mod-est longevity. In a secondary analysis of theDiabetes Prevention Program (DPP), a largeclinical trial designed to compare strategies forT2DM prevention in individuals at high risk forT2DM, parental longevity was associated with adelay in the incidence of T2DM in the offspring,with the children of parents with longest lifespans experiencing the greatest delay in diseaseonset (Florez et al. 2011). The effect of parentallife span on diabetes prevention was found to bejust as strong as the effect of metformin, anantidiabetic drug used in this study (Florezet al. 2011). These results show that extendedparental life span is strongly associated withbetter health outcomes in the offspring, evenin populations who achieve less extreme degreesof longevity.

Mechanisms for Exceptional Longevity in Humans

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Although environmental influences mayhave a significant effect on health and life spanin the general population, this does not seem tobe the case in centenarians. A study that com-pared individuals with exceptional longevityto their contemporaries who did not achievelongevity found that centenarians were as likelyas their shorter-lived peers to have been over-weight or obese (Rajpathak et al. 2011). Further-more, the proportion of centenarians whosmoked, consumed alcohol daily, had not par-ticipated in regular physical activity, or had notfollowed a low-calorie diet throughout theirmiddle age was similar to that among theirpeers from the same birth cohort. In fact, asmany as 60% of male and 30% of female cen-tenarians had been smokers (Rajpathak et al.2011). Thus, the centenarians had not engagedin a healthier lifestyle compared with theirpeers. This supports the notion that peoplewith exceptional longevity possess genomic fac-tors that protect them from the environmentalinfluences that may be detrimental to health.

GENETICS OF EXCEPTIONAL LONGEVITY

For more than a decade, centenarian popula-tions of diverse Americans, as well as ethni-cally homogeneous populations of Mormons,Ashkenazi Jews (AJs), Icelandics, OkinawanJapanese, Italians, Irish, and Dutch, among oth-ers, have served as cohorts for studies to identifylongevity genes or longevity-associated biolog-ical pathways. These studies relied on candidategenes and genome-wide association studies(GWAS) that included genotyping of large pop-ulations. One of the strengths of GWAS com-pared with the candidate gene approach is thatthese studies are unbiased. Their results mayprovide insights into novel mechanisms of lon-gevity. Several research groups have conductedGWAS for longevity (Beekman et al. 2010; Se-bastiani et al. 2012), yet none yielded significantresults after appropriate statistical correctionsfor multiple comparisons were applied. One ex-ception was the finding of the APOE2 genotype,although its identification may have been theresult of ascertainment bias, because individ-uals with the APOE4 allele, who are at higher

risk for developing Alzheimer’s dementia, areless likely to be recruited into population stud-ies (Nebel et al. 2011).

There are several explanations for these dis-appointing results. First, relying on commongenetic variants that occur at frequencies from5% to 49% in the population to study such a rareevent as exceptional longevity (one that occursat a rate of 1/6000–1/10,000 in the general pop-ulation) may result in missing the rarer longev-ity-associated genotypes. This also underscoresthe need for exon or whole-genome sequencingto discover rare mutations. Second, applyingGWAS to genetically diverse populations re-quires a very large study cohort to accountfor genomic diversity and to identify relativelyrare genetic variants. Thus, most studies havelacked sufficient power for such discoveries.

Following this logic, it is not surprising thatmany important genetic discoveries were madein populations that show comparatively smalllevels of genetic diversity. One such exampleis the Icelandic population, which originatedfrom a small number of founders and expandedto �500,000 people. Others include the Amishand AJs, a larger population (Barzilai et al. 2003;Atzmon et al. 2008, 2009b, 2010; Suh et al. 2008).The advantage of studying a genetically homo-geneous population was exemplified by a recentstudy, which showed that the addition of each AJsubject contributed 20 times more genetic vari-ability to the cohort as compared with adding aEuropean subject to a cohort of European originof identical sample size (Carmi et al. 2014).

There are several ways in which geneticallysimilar populations can contribute to geneticand biological discovery. One is if the popula-tion has a higher frequency of carriers of aparticular genotype and its associated pheno-type caused by the founder effect, as is the casewith breast cancer caused by mutations in theBRCA genes among AJ women. Another is thatsingle nucleotide polymorphisms (SNPs) thatare novel or rare in the general population willoccur at higher frequencies in a homogenouspopulation. This will result in the associatedrare phenotype, such as longevity, to be moreamenable to withstand the rigorous statisti-cal analysis that is performed on genetic data.



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Third, many SNPs that are statistically signifi-cant, but below the threshold for GWAS, maystill be relevant. Last, it is possible that numer-ous SNPs contribute in combination to the phe-notype. Indeed, Sebastiani et al. (2012) haveidentified 281 SNPs that can distinguish cente-narians from controls.

Although discovery of longevity-associatedgenes has been met with several challenges,many genes have been identified that are asso-ciated with risk for CVD, AD, T2DM, and oth-er age-related diseases. One attractive hypoth-esis has been that centenarians lack thesedisease-associated genes, thus being protectedby a more “perfect genome.” However, it hasbecome clear from GWAS that centenariansharbor as many disease-associated genotypesas controls. Furthermore, a whole-genome se-quence analysis of 44 centenarians revealed thatthis group carried a total of 227 autosomal and7 X-chromosome coding single nucleotide var-iants (SNVs) that are likely to cause diseaseaccording to the ClinVar database (Freuden-berg-Hua et al. 2014). Among these are variantsassociated with Parkinson’s disease, AD, neuro-degenerative diseases, neoplastic, and cardiacdiseases. Despite .95 years of exposure tothese risky genotypes, none of the centenariansshowed any of the diseases for which they weregenetic carriers. These observations led to theconclusion that there are longevity-associatedprotective genotypes in centenarians that delayaging or specifically protect against the mani-festation of age-related diseases.

Although the GWAS approach did not proveto be particularly helpful in identifying longev-ity genes, some success stories have emergedthrough the application of the candidate geneapproach. Several genes were selected for inves-tigation because they were previously implicat-ed in aging, and SNPs within these genes weresuggested to be linked with longevity. These in-cluded PON1 (Bonafe et al. 2002; Rea et al. 2004;Franceschi et al. 2005; Marchegiani et al. 2006;Tan et al. 2006), insulin-like growth factor 1(IGF-1) (Bonafe et al. 2003; Kojima et al. 2004;van Heemst et al. 2005), PAPR-1, cytokine genes,genes that code for enzymatic antioxidants suchas superoxide dismutases (Andersen et al. 1998;

Mecocci et al. 2000), and components of lipidmetabolism (Barzilai et al. 2006; Vergani et al.2006). Other genes that have been implicated inhuman aging, and not only longevity, are updat-ed on the Aging Gene Database (see genomics.senescence.info/genes).

However, not all discoveries resulted in im-proved understanding of the biology of aging.One of the most notable discoveries of a longev-ity-associated gene, which has been validated bynumerous research groups, is the FOXO3a ge-notype. As summarized by Kahn (2014), theFOXO3a genotypes are rather common, theidentified SNPs within the gene localize to in-tronic or noncoding regions, and despite se-quencing of the whole gene by several groups,no functional mutations have thus far beenidentified in the regions of the gene that wouldpredict altered protein function. Furthermore,assays of cells with the FOXO3a genotype vari-ants also have not been, thus far, associated withfunctional changes. Finally, no identifiable phe-notype has yet been linked with these FOXO3agenotypes and they have not been related to riskor protection from disease. In fact, a panel ofexperts did not agree on whether a drug thatdisplaces FOXO3a from the nucleus to the cy-toplasm would induce longevity or shorten thelife span (Monsalve and Olmos 2011). The ex-ample of FOXO3a shows that even a validatedgenotype does not always translate into betterunderstanding of the biology of longevity.

There are also other challenges that re-searchers face studying longevity. In additionto the usual problems and pitfalls of associationstudies, particularly in the new age of “big data”brought on by whole-genome sequencing (Law-rence et al. 2005), there is another problem thatis particular to longevity studies—that of iden-tifying appropriate controls for a cohort ofexceptionally long-lived individuals. This hasbeen a challenge because the ideal controls, in-dividuals of the same birth cohort as the cen-tenarians but who have not achieved exception-al longevity, are all deceased. One approach toovercome this challenge has been to rely on theinnovative experimental design in which theprogeny of centenarians, who have inheritedabout half of their genome from the centenarian



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parent, are compared with their spouses who donot have a parental history of longevity and thuscan serve as matched controls (Barzilai et al.2001).

GENOMIC DISCOVERIES ANDMECHANISMS FOR EXCEPTIONALLONGEVITY

The Longevity Genes Project (LGP) and Lon-Genity are studies that include families of AJswith exceptional longevity. Because longevitycarries a substantial genetic component, thesestudies conduct genomic and detailed pheno-type analyses in the families with exceptionallongevity in an effort to determine the func-tions of genes of interest. Using the candidategene approach in this AJ cohort, several favor-able homozygous genotypes were identified inmultiple genes, which were associated withunique biological phenotypes.

The cholesterol ester transfer protein(CETP) gene codon 405 isoleucine to valine var-iant was associated with low levels of plasmaCETP, high levels of high-density lipoprotein(HDL) cholesterol, and large lipoprotein parti-cle size. This genotype was also shown to beprotective against cognitive decline and AD inan independent diverse population (Sanderset al. 2010). This same genotype was validatedby another research group in an Italian popula-tion (Vergani et al. 2006). Three other genotypesin the CETP gene were also found to be signifi-cantly associated with longevity in the LLFSstudy. Although none of the other studies haveconfirmed these findings, it is important to keepin mind that a particular SNP may not show asimilar phenotype in all populations. Therefore,the biological phenotype itself should be testedfor association with longevity rather than a par-ticular SNP that may have differential expres-sion in varying populations. Further complicat-ing matters is the possibility that the gene withthe significant action may be in linkage disequi-librium with the SNP and that there may begenetic variations at that associated locus.

Another lipid-related genotype, homozy-gosity for the apolipoprotein C-3 (APOC-3)–641 C allele was also associated with exceptional

longevity in AJs (Atzmon et al. 2006). It tooshowed a unique lipid phenotype and low levelsof plasma APOC-3 (Atzmon et al. 2006). Ina striking example of validation, carriers of adifferent APOC3 genotype in a homogenousPennsylvania Amish population also showedlow APOC-3 levels, a favorable lipid phenotype,better arterial health score, and enhanced lon-gevity (Pollin et al. 2008). These findings showthe power of discovery in selected geneticallyhomogeneous populations. The APOC-3 geno-type was also identified to be related to excep-tional longevity in the LLFS, but the phenotypeassociated with this SNP has not yet been re-vealed.

ADIPOQ is another longevity-associatedgenotype. Adiponectin is a fat-derived peptidewith powerful effects on lipids and metabo-lism. A deletion at þ2019 in the adiponectin(ADIPOQ) gene was associated in the AJ co-horts with longevity, which was also related toa phenotype of high adiponectin levels, inde-pendent of fat mass (Atzmon et al. 2008).

A longevity-associated genotype whose dis-covery has already made an impact on clinicalpractice is that of the thyroid stimulating hor-mone receptor (TSHR) (Atzmon et al. 2009a,b).The metabolic rate theory of aging suggests that,in nature, there exists an inverse relationshipbetween basal metabolic rate and aging, withseveral hypothyroid mammalian models show-ing longer life span. Centenarians have higherplasma thyroid stimulating hormone (TSH)levels, although they are not hypothyroid, andtheir offspring also show this phenotype withsignificant hereditability (Atzmon et al. 2009a;Rozing et al. 2010). These clinical features havebeen supported by a National Health and Nu-trition Examination Survey (NHANES III) con-ducted across the United States and led to therecommendation to not supplement olderadults with mild elevations in TSH with thyroidhormone (Tabatabaie and Surks 2013).

In nature, disruption of the growth hor-mone (GH)/IGF-1 action has led to extensionof life span. Spontaneous and experimentallyinduced partial disruptions of the GH/IGF-1pathway, including genetic alterations, are asso-ciated with a small body size (dwarfism) across



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species (Brown-Borg et al. 1996). Thus, smalldogs have longer life spans than large dogs (Sa-maras and Elrick 2002). Models of IGF-1 defi-ciency show numerous indices of delayed aging,including enhanced stress resistance and a ma-jor increase in life span (Kenyon et al. 1993;Brown-Borg et al. 1996). On the other hand,reduced levels of IGF-1 in humans, while pro-tective against cancer, have been linked withhigher risk for CVD and diabetes (Sandhuet al. 2002; Burgers et al. 2011), suggesting amore complex physiological role for IGF-1 inhumans. Several SNPs in genes within the insu-lin/IGF-1-signaling pathway have been associ-ated with and validated in exceptional longevity,but, for the most part, no specific phenotyperelated to these SNPs has been identified (Paw-likowska et al. 2009). An exception to this hasbeen the identification of a functional IGF-1receptor (IGF-1R) gene mutation discovered af-ter sequencing the IGF-1 and IGF-1R genes ofcentenarians (Suh et al. 2008). Heterozygousmutations in the IGF-1R gene have been over-represented among centenarians comparedwith the controls without familial longevityand have been associated with high-serumIGF-1 levels in the setting of reduced activityof the IGF-1R, as measured in transformed lym-phocytes (Tazearslan et al. 2011). Partial IGF-1resistance conferred by these longevity-associ-ated IGF-1R genotypes was confirmed in astudy conducted on wild-type cells transformedwith the mutant genes (Tazearslan et al. 2011).A particular IGF-1R genotype was also associ-ated with longevity in the LLFS; however, itsassociated phenotype has not yet been defined.

Another example that highlights the impor-tance of GH/IGF-1 signaling in extended healthspan comes from a population of Laron Dwarfs,who are carriers of a rare mutation in the GHreceptor (GHR) gene that results in GHR defi-ciency. A group with this genotype was studiedin Ecuador and appears to have a negligibleprevalence of type 2 diabetes mellitus and can-cer (Guevara-Aguirre et al. 2011). Althoughthey did not live long, clearly they have beenprotected from major age-related diseases.

Finally, among females with exceptionallongevity, those with IGF-1 levels below the

median exhibited significantly longer survivalcompared with those with levels above the me-dian (Fig. 2) (Milman et al. 2014). However, thisrelationship between IGF-1 levels and survivalwas not observed in males with exceptional lon-gevity. On the other hand, among males andfemales who achieved longevity and had a histo-ry of cancer, lower IGF-1 levels predicted longersurvival (Milman et al. 2014). Thus, low IGF-1levels predict life expectancy in exceptionallylong-lived individuals, supporting the role ofthe GH/IGF-1 pathway in exceptional longevity.

Interest in telomeres and their associationwith aging led to significant research effortsaimed at identifying the role of telomere lengthin exceptional longevity. Telomere length ormass assessment showed that centenarianshave longer telomeres, that this length is inher-ited in their offspring, and is associated withdecreased incidence of the metabolic syndrome(MS), T2DM, and cognitive decline (Atzmonet al. 2010). This longevity-associated telomerephenotype has also been related to a genetic“fingerprint” in the telomerase genes in cente-narians (Atzmon et al. 2010).

Other genomic mechanisms, no doubt, alsocontribute to aging, including epigenomic var-iations. Sirtuins, resveratrol, and other specificactivators have been used to induce histone de-acetylation and activation of the SIRT1 gene,thereby resulting in longevity in a variety ofanimal models and in high-fat fed mice. How-ever, no significant association between SIRT1genotypes and longevity has been reported inhumans thus far (Han et al. 2014). Methylationpatterns have been noted to change with agingand may affect the transcribed DNA. Initialstudies have shown significant differences inmethylation patterns between centenarians andyounger controls, with several groups currentlypursuing this line of research. Finally, longevity-associated microRNAs have been identified, buttheireffects still need to be determined (Gombaret al. 2012).

EXCEPTIONAL LONGEVITY LEADING TOAGE-DELAYING DRUGSThe goal of longevity research is to identifypathways that are relevant to human aging and



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to develop drugs that will delay aging by target-ing these pathways. Longevity and extension ofhealthy life span have been achieved in modelsvia a variety of genetic manipulations, drugs,and environmental influences, thereby provid-ing the preclinical foundation needed to pro-ceed to drug development. The main obstaclefacing the development of drugs for the treat-ment of aging is the fact that the U.S. Food andDrug Administration (FDA) does not consideraging as a preventable condition. Even if therewould be a popular demand for drugs thatdelay aging, the pharmaceutical industry wouldnot develop drugs that will not be reimbursedby health insurance companies. The same wastrue for hypertension, until studies showed thatlowering blood pressure prevented CVD, in-cluding strokes.

The pharmaceutical industry has relied ongenetic discoveries made in longevity studies,as well as other studies, to identify individualswho have naturally occurring genetic variants ormutations that confer desirable phenotypes.The goals for pharmaceutical development isto create drugs whose actions would mimicthose of the favorable genetic variants. Observ-ing the carriers of these genetic variants for any

detrimental health effects informs drug makersof any potential side effects that may arise froma drug that targets the desired pathway. For ex-ample, the observation that centenarians areenriched with a unique CETP genotype thatexposes them to a lifetime of lower CETP levelsthat is also associated with high HDL level andlarge lipoprotein particle size, suggests that de-creased CETP function is safe (Barzilai et al.2003). In fact, a CETP inhibitor is currentlybeing tested in a phase 3 trial by a leading phar-maceutical company (Cannon et al. 2010). Sim-ilar observations were made about the APOC-3protein, and an APOC-3 inhibitor is also beingtested in a phase 3 trial by another pharmaceu-tical company (Graham et al. 2013; Lee et al.2013).

Another class of agents whose actions on ag-ing may be predicted through longevity researchare monoclonal antibodies directed against theIGF-1 receptor. These were initially developedby several pharmaceutical industries as antineo-plastic therapies; however, they were not suc-cessful at treating cancer because of a significantdegree of mutagenesis within cancer cells thateventually made them resistant to these drugs.Nonetheless, these compounds are available for

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Figure 2. Kaplan–Meier survival curves for females with IGF-1 levels above and below the median. (FromMilman et al. 2014; adapted, with permission.)



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preclinical testing in aging research. Similarly,the GH/IGF-1 pathway, which may be impor-tant for human aging, can be targeted by theGHR antagonist that is currently in clinicaluse for the treatment of acromegaly, a conditionof GH excess (Kopchick 2003). Although theabove-mentioned therapeutics are not presentlybeing developed for longevity, these drugs maybe tested in the future for the indication of de-laying aging and age-associated diseases.

Other drugs may target aging more specifi-cally, although they are in clinical use for otherindications. One example is a class of drugs thatinhibit the mammalian target of rapamycin(mTOR) enzyme. These drugs are primarilyused as immune modulators post organ trans-plantation, but recently also have been shown toincrease the immune response to vaccinations inthe elderly (Mannick et al. 2014), thereby dem-onstrating their potential utility in the treatmentof health conditions associated with aging.

Another drug of interest is metformin, thefirst line drug treatment for T2DM. Several re-search groups tested the effect of metformin onaging and showed that it caused extension in lifespan and health span in many rodent models(Anisimov et al. 2008, 2010, 2011; Smith et al.2010; Martin-Montalvo et al. 2013). Metforminalso extended the life span of nematodes (Ca-breiro et al. 2013), suggesting that its action ismediated via an evolutionary conserved mech-anism. Numerous investigators looked at thepotential antiaging effects of this drug in pop-ulations treated with metformin for T2DM. Thelarge United Kingdom Prospective DiabetesStudy (UKPDS) convincingly showed that met-formin reduced the incidence of CVD (Holmanet al. 2008; Anfossi et al. 2010). This finding hasbeen validated and reproduced by other studiesand meta-analysis (Johnson et al. 2005; La-manna et al. 2011; Roumie et al. 2012; Honget al. 2013; Whittington et al. 2013). In addi-tion, a number of studies suggested that met-formin use is associated with a decreased inci-dence of cancer (Libby et al. 2009; Landmanet al. 2010; Lee et al. 2011; Monami et al.2011; Tseng 2012), with many animal and cellmodels demonstrating the inhibitory effects ofmetformin on tumorigenesis (Seibel et al. 2008;

Tosca et al. 2010; Liu et al. 2011; Salani et al.2012; Anisimov and Bartke 2013; Karnevi et al.2013; Quinn et al. 2013). The proposed mech-anisms of action for metformin’s effect on inhib-iting tumorigenesis include decrease in insulinproduction and its action, decrease in IGF-1signaling, and AMP-activated protein kinase(AMPK) activation.

In the future, other compounds discoveredto be important for longevity may be developedinto drugs. For example, the level of humanin, amitochondrial-derived peptide, decreases withaging but has been shown to increase up tothreefold in the offspring of centenarians (Mu-zumdar et al. 2009), thus making it an attractivecandidate for drug development.

CONCLUDING REMARKS

This article shows that, via the use of biologicand genetic experimental methods, scientistscan determine why some people age moreslowly or more rapidly than others. Such dis-coveries in humans, as opposed to those in oth-er animal models, have the advantage of beingdirectly relevant to human longevity and can berelied on by pharmaceutical developers lookingto establish the safety of drugs whose actionsmimic the function of the genetic variantsfound in centenarians. Thus it follows that iffunctional mutations or SNPs that are morecommon in centenarians are also deemed safein that population, then drugs that mimic thedesired actions are worth developing. This kindof drug development should result in uniquedrugs that target not only specific diseases butalso aging. The barrier for development ofdrugs that target aging is that, at present, agingis not an indication for treatment by the FDA.There is an urgent need to change this paradigmto accelerate drug development and realize thelongevity dividend.

ACKNOWLEDGMENTS

S.M. is supported by the National Center forAdvancing Translational Sciences of the Nation-al Institutes of Health under Award NumberKL2TR001071. N.B. is supported by Grants



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from the National Institutes of Health (NIH)(P01AG021654), The Nathan Shock Cen-ter of Excellence for the Biology of Aging(P30AG038072), the Glenn Center for the Bi-ology of Human Aging (Paul Glenn Founda-tion for Medical Research), NIH R37 AG18381(Barzilai Merit Award), and NIH/NIA 1R01AG044829. The content is solely the re-sponsibility of the authors and does not neces-sary represent the official views of the NIH.

REFERENCES

Adams ER, Nolan VG, Andersen SL, Perls TT, Terry DF.2008. Centenarian offspring: Start healthier and stayhealthier. J Am Geriatr Soc 56: 2089–2092.

Ailshire JA, Beltran-Sanchez H, Crimmins EM. 2015. Be-coming centenarians: Disease and functioning trajecto-ries of older US Adults as they survive to 100. J Gerontol ABiol Sci Med Sci 70: 193–201.

Altmann-Schneider I, van der Grond J, Slagboom PE,Westendorp RG, Maier AB, van Buchem MA, de CraenAJ. 2012. Lower susceptibility to cerebral small vesseldisease in human familial longevity: The Leiden Long-evity Study. Stroke 44: 9–14.

Andersen HR, Jeune B, Nybo H, Nielsen JB, Andersen-Ran-berg K, Grandjean P. 1998. Low activity of superoxidedismutase and high activity of glutathione reductase inerythrocytes from centenarians. Age Ageing 27: 643–648.

Andersen SL, Sebastiani P, Dworkis DA, Feldman L, PerlsTT. 2012. Health span approximates life span amongmany supercentenarians: Compression of morbidity atthe approximate limit of life span. J Gerontol A Biol SciMed Sci 67: 395–405.

Anderson KM, Odell PM, Wilson PW, Kannel WB. 1991.Cardiovascular disease risk profiles. Am Heart J 121:293–298.

Anfossi G, Russo I, Bonomo K, Trovati M. 2010. The car-diovascular effects of metformin: Further reasons to con-sider an old drug as a cornerstone in the therapy of type 2diabetes mellitus. Curr Vasc Pharmacol 8: 327–337.

Anisimov VN, Bartke A. 2013. The key role of growth hor-mone-insulin-IGF-1 signaling in aging and cancer. CritRev Oncol Hematol 87: 201–223.

Anisimov VN, Berstein LM, Egormin PA, Piskunova TS,Popovich IG, Zabezhinski MA, Tyndyk ML, YurovaMV, Kovalenko IG, Poroshina TE, et al. 2008. Metforminslows down aging and extends life span of female SHRmice. Cell Cycle 7: 2769–2773.

Anisimov VN, Egormin PA, Piskunova TS, Popovich IG,Tyndyk ML, Yurova MN, Zabezhinski MA, Anikin IV,Karkach AS, Romanyukha AA. 2010. Metformin extendslife span of HER-2/neu transgenic mice and in combi-nation with melatonin inhibits growth of transplantabletumors in vivo. Cell Cycle 9: 188–197.

Anisimov VN, Berstein LM, Popovich IG, Zabezhinski MA,Egormin PA, Piskunova TS, Semenchenko AV, TyndykML, Yurova MN, Kovalenko IG, et al. 2011. If started

early in life, metformin treatment increases life spanand postpones tumors in female SHR mice. Aging (Alba-ny NY) 3: 148–157.

Atzmon G, Schechter C, Greiner W, Davidson D, Rennert G,Barzilai N. 2004. Clinical phenotype of families with lon-gevity. J Am Geriatr Soc 52: 274–277.

Atzmon G, Rincon M, Schechter CB, Shuldiner AR, LiptonRB, Bergman A, Barzilai N. 2006. Lipoprotein genotypeand conserved pathway for exceptional longevity in hu-mans. PLoS Biol 4: e113.

Atzmon G, Pollin TI, Crandall J, Tanner K, Schechter CB,Scherer PE, Rincon M, Siegel G, Katz M, Lipton RB, et al.2008. Adiponectin levels and genotype: A potential reg-ulator of life span in humans. J Gerontol A Biol Sci MedSci 63: 447–453.

Atzmon G, Barzilai N, Hollowell JG, Surks MI, Gabriely I.2009a. Extreme longevity is associated with increasedserum thyrotropin. J Clin Endocrinol Metab 94: 1251–1254.

Atzmon G, Barzilai N, Surks MI, Gabriely I. 2009b. Geneticpredisposition to elevated serum thyrotropin is associat-ed with exceptional longevity. J Clin Endocrinol Metab 94:4768–4775.

Atzmon G, Cho M, Cawthon RM, Budagov T, Katz M, YangX, Siegel G, Bergman A, Huffman DM, Schechter CB, etal. 2010. Evolution in health and medicine Sackler collo-quium: Genetic variation in human telomerase is associ-ated with telomere length in Ashkenazi centenarians.Proc Natl Acad Sci 107: 1710–1717.

Barzilai N, Gabriely I, Gabriely M, Iankowitz N, Sorkin JD.2001. Offspring of centenarians have a favorable lipidprofile. J Am Geriatr Soc 49: 76–79.

Barzilai N, Atzmon G, Schechter C, Schaefer EJ, Cupples AL,Lipton R, Cheng S, Shuldiner AR. 2003. Unique lipopro-tein phenotype and genotype associated with exceptionallongevity. JAMA 290: 2030–2040.

Barzilai N, Atzmon G, Derby CA, Bauman JM, Lipton RB.2006. A genotype of exceptional longevity is associatedwith preservation of cognitive function. Neurology 67:2170–2175.

Beekman M, Nederstigt C, Suchiman HE, Kremer D, vander Breggen R, Lakenberg N, Alemayehu WG, de CraenAJ, Westendorp RG, Boomsma DI, et al. 2010. Genome-wide association study (GWAS)–identified disease riskalleles do not compromise human longevity. Proc NatlAcad Sci 107: 18046–18049.

Bonafe M, Marchegiani F, Cardelli M, Olivieri F, CavalloneL, Giovagnetti S, Pieri C, Marra M, Antonicelli R, TroianoL, et al. 2002. Genetic analysis of paraoxonase (PON1)locus reveals an increased frequency of Arg192 allele incentenarians. Eur J Hum Genet 10: 292–296.

Bonafe M, Barbieri M, Marchegiani F, Olivieri F, Ragno E,Giampieri C, Mugianesi E, Centurelli M, Franceschi C,Paolisso G. 2003. Polymorphic variants of insulin-likegrowth factor I (IGF-I) receptor and phosphoinositide3-kinase genes affect IGF-I plasma levels and human lon-gevity: Cues for an evolutionarily conserved mechanismof life span control. J Clin Endocrinol Metab 88: 3299–3304.

Brown-Borg HM, Borg KE, Meliska CJ, Bartke A. 1996.Dwarf mice and the ageing process. Nature 384: 33.



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



Burgers AM, Biermasz NR, Schoones JW, Pereira AM, Re-nehan AG, Zwahlen M, Egger M, Dekkers OM. 2011.Meta-analysis and dose-response metaregression: Circu-lating insulin-like growth factor I (IGF-I) and mortality. JClin Endocrinol Metab 96: 2912–2920.

Cabreiro F, Au C, Leung KY, Vergara-Irigaray N, CochemeHM, Noori T, Weinkove D, Schuster E, Greene ND, GemsD. 2013. Metformin retards aging in C. elegans by alteringmicrobial folate and methionine metabolism. Cell 153:228–239.

Cannon CP, Shah S, Dansky HM, Davidson M, Brinton EA,Gotto AM, Stepanavage M, Liu SX, Gibbons P, Ashraf TB,et al. 2010. Safety of anacetrapib in patients with or athigh risk for coronary heart disease. N Engl J Med 363:2406–2415.

Carmi S, Hui KY, Kochav E, Liu X, Xue J, Grady F, Guha S,Upadhyay K, Ben-Avraham D, Mukherjee S, et al. 2014.Sequencing an Ashkenazi reference panel supports pop-ulation-targeted personal genomics and illuminates Jew-ish and European origins. Nat Commun 5: 4835.

Evans CJ, Ho Y, Daveson BA, Hall S, Higginson IJ, Gao W.2014. Place and cause of death in centenarians: A popu-lation-based observational study in England, 2001 to2010. PLoS Med 11: e1001653.

Florez H, Ma Y, Crandall JP, Perreault L, Marcovina SM, BrayGA, Saudek CD, Barrett-Connor E, Knowler WC. 2011.Parental longevity and diabetes risk in the Diabetes Pre-vention Program. J Gerontol A Biol Sci Med Sci 66: 1211–1217.

Franceschi C, Olivieri F, Marchegiani F, Cardelli M, Caval-lone L, Capri M, Salvioli S, Valensin S, De Benedictis G,Di Iorio A, et al. 2005. Genes involved in immune re-sponse/inflammation, IGF1/insulin pathway and re-sponse to oxidative stress play a major role in the geneticsof human longevity: The lesson of centenarians. MechAgeing Dev 126: 351–361.

Freudenberg-Hua Y, Freudenberg J, Vacic V, Abhyankar A,Emde AK, Ben-Avraham D, Barzilai N, Oschwald D,Christen E, Koppel J, et al. 2014. Disease variants in ge-nomes of 44 centenarians. Mol Genet Genomic Med 2:438–450.

Gavrilov L, Gavrilova N, Semyonova V, Evdokushkina G.2001. Parental age effects on human longevity. In AnnualMeeting of the Gerontological Society of America, Chicago,November 15–18.

Goldman DP, Cutler D, Rowe JW, Michaud PC, Sullivan J,Peneva D, Olshansky SJ. 2013. Substantial health andeconomic returns from delayed aging may warrant anew focus for medical research. Health Aff (Millwood)32: 1698–1705.

Gombar S, Jung HJ, Dong F, Calder B, Atzmon G, Barzilai N,Tian XL, Pothof J, Hoeijmakers JH, Campisi J, et al. 2012.Comprehensive microRNA profiling in B-cells of humancentenarians by massively parallel sequencing. BMC Ge-nomics 13: 353.

Graham MJ, Lee RG, Bell TA III, Fu W, Mullick AE, Alex-ander VJ, Singleton W, Viney N, Geary R, Su J, et al. 2013.Antisense oligonucleotide inhibition of apolipoproteinC-III reduces plasma triglycerides in rodents, nonhumanprimates, and humans. Circ Res 112: 1479–1490.

Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M,Wei M, Madia F, Cheng CW, Hwang D, Martin-Montalvo

A, Saavedra J, Ingles S, et al. 2011. Growth hormonereceptor deficiency is associated with a major reductionin pro-aging signaling, cancer, and diabetes in humans.Sci Transl Med 3: 70ra13.

Han J, Atzmon G, Barzilai N, Suh Y. 2014. Genetic variationin Sirtuin 1 (SIRT1) is associated with lipid profiles butnot with longevity in Ashkenazi Jews. Transl Res 165:480–481.

Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA.2008. 10-year follow-up of intensive glucose control intype 2 diabetes. N Engl J Med 359: 1577–1589.

Hong J, Zhang Y, Lai S, Lv A, Su Q, Dong Y, Zhou Z, Tang W,Zhao J, Cui L, et al. 2013. Effects of metformin versusglipizide on cardiovascular outcomes in patients withtype 2 diabetes and coronary artery disease. DiabetesCare 36: 1304–1311.

Ismail KNL, Sebastiani P, Milman S, Perls TT, Barzilai N.2014. Individuals with exceptional longevity exhibit in-creased health span and delayed onset of age-related dis-eases. In Presidential Poster Session of the American Geri-atrics Society Annual Meeting, Orlando, FL, May 15–18.

Johnson JA, Simpson SH, Toth EL, Majumdar SR. 2005.Reduced cardiovascular morbidity and mortality associ-ated with metformin use in subjects with type 2 diabetes.Diabet Med 22: 497–502.

Kahn AJ. 2014. FOXO3 and related transcription factors indevelopment, aging, and exceptional longevity. J GerontolA Biol Sci Med Sci 70: 421–425.

Karnevi E, Said K, Andersson R, Rosendahl AH. 2013. Met-formin-mediated growth inhibition involves suppressionof the IGF-I receptor signalling pathway in human pan-creatic cancer cells. BMC Cancer 13: 235.

Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R. 1993.A C. elegans mutant that lives twice as long as wild type.Nature 366: 461–464.

Kojima T, Kamei H, Aizu T, Arai Y, Takayama M, NakazawaS, Ebihara Y, Inagaki H, Masui Y, Gondo Y, et al. 2004.Association analysis between longevity in the Japanesepopulation and polymorphic variants of genes involvedin insulin and insulin-like growth factor 1 signaling path-ways. Exp Gerontol 39: 1595–1598.

Kopchick JJ. 2003. Discovery and mechanism of action ofpegvisomant. Eur J Endocrinol 148: S21–25.

Lamanna C, Monami M, Marchionni N, Mannucci E. 2011.Effect of metformin on cardiovascular events and mor-tality: A meta-analysis of randomized clinical trials. Di-abetes Obes Metab 13: 221–228.

Landman GW, Kleefstra N, van Hateren KJ, Groenier KH,Gans RO, Bilo HJ. 2010. Metformin associated with lowercancer mortality in type 2 diabetes: ZODIAC-16. Diabe-tes Care 33: 322–326.

Lawrence RW, Evans DM, Cardon LR. 2005. Prospects andpitfalls in whole genome association studies. Philos TransR Soc Lond B Biol Sci 360: 1589–1595.

Lee MS, Hsu CC, Wahlqvist ML, Tsai HN, Chang YH,Huang YC. 2011. Type 2 diabetes increases and metfor-min reduces total, colorectal, liver and pancreatic cancerincidences in Taiwanese: A representative populationprospective cohort study of 800,000 individuals. BMCCancer 11: 20.



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



Lee RG, Crosby J, Baker BF, Graham MJ, Crooke RM. 2013.Antisense technology: An emerging platform for cardio-vascular disease therapeutics. J Cardiovasc Transl Res 6:969–980.

Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD,Evans JM. 2009. New users of metformin are at low risk ofincident cancer: A cohort study among people with type2 diabetes. Diabetes Care 32: 1620–1625.

Lipton RB, Hirsch J, Katz MJ, Wang C, Sanders AE, VergheseJ, Barzilai N, Derby CA. 2010. Exceptional parental lon-gevity associated with lower risk of Alzheimer’s diseaseand memory decline. J Am Geriatr Soc 58: 1043–1049.

Liu B, Fan Z, Edgerton SM, Yang X, Lind SE, Thor AD.2011. Potent anti-proliferative effects of metformin ontrastuzumab-resistant breast cancer cells via inhibitionof erbB2/IGF-1 receptor interactions. Cell Cycle 10:2959–2966.

Mannick JB, Del Giudice G, Lattanzi M, Valiante NM,Praestgaard J, Huang B, Lonetto MA, Maecker HT, Ko-varik J, Carson S, et al. 2014. mTOR inhibition improvesimmune function in the elderly. Sci Transl Med 6:268ra179.

Marchegiani F, Marra M, Spazzafumo L, James RW, BoemiM, Olivieri F, Cardelli M, Cavallone L, Bonfigli AR, Fran-ceschi C. 2006. Paraoxonase activity and genotype pre-dispose to successful aging. J Gerontol A Biol Sci Med Sci61: 541–546.

Martin GM. 2005. Genetic modulation of senescent pheno-types in Homo sapiens. Cell 120: 523–532.

Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH,Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM,Minor RK, Blouin MJ, et al. 2013. Metformin improveshealthspan and lifespan in mice. Nat Commun 4: 2192.

Mecocci P, Polidori MC, Troiano L, Cherubini A, CecchettiR, Pini G, Straatman M, Monti D, Stahl W, Sies H, et al.2000. Plasma antioxidants and longevity: A study onhealthy centenarians. Free Radic Biol Med 28: 1243–1248.

Milman S, Atzmon G, Huffman DM, Wan J, Crandall JP,Cohen P, Barzilai N. 2014. Low insulin-like growth factor-1 level predicts survival in humans with exceptional lon-gevity. Aging Cell 13: 769–771.

Monami M, Colombi C, Balzi D, Dicembrini I, Giannini S,Melani C, Vitale V, Romano D, Barchielli A, MarchionniN, et al. 2011. Metformin and cancer occurrence in insu-lin-treated type 2 diabetic patients. Diabetes Care 34:129–131.

Monsalve M, Olmos Y. 2011. The complex biology ofFOXO. Curr Drug Targets 12: 1322–1350.

Muzumdar RH, Huffman DM, Atzmon G, Buettner C,Cobb LJ, Fishman S, Budagov T, Cui L, Einstein FH,Poduval A, et al. 2009. Humanin: A novel central regula-tor of peripheral insulin action. PLoS ONE 4: e6334.

Nebel A, Kleindorp R, Caliebe A, Nothnagel M, Blanche H,Junge O, Wittig M, Ellinghaus D, Flachsbart F, Wich-mann HE, et al. 2011. A genome-wide association studyconfirms APOE as the major gene influencing survival inlong-lived individuals. Mech Ageing Dev 132: 324–330.

Pawlikowska L, Hu D, Huntsman S, Sung A, Chu C, Chen J,Joyner AH, Schork NJ, Hsueh WC, Reiner AP, et al. 2009.Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. Aging Cell8: 460–472.

Perls TT, Bubrick E, Wager CG, Vijg J, Kruglyak L. 1998.Siblings of centenarians live longer. Lancet 351: 1560.

Perls TT, Wilmoth J, Levenson R, Drinkwater M, Cohen M,Bogan H, Joyce E, Brewster S, Kunkel L, Puca A. 2002.Life-long sustained mortality advantage of siblings ofcentenarians. Proc Natl Acad Sci 99: 8442–8447.

Pollin TI, Damcott CM, Shen H, Ott SH, Shelton J, Horen-stein RB, Post W, McLenithan JC, Bielak LF, Peyser PA, etal. 2008. A null mutation in human APOC3 confers afavorable plasma lipid profile and apparent cardioprotec-tion. Science 322: 1702–1705.

Quinn BJ, Dallos M, Kitagawa H, Kunnumakkara AB, Mem-mott RM, Hollander MC, Gills JJ, Dennis PA. 2013. In-hibition of lung tumorigenesis by metformin is associat-ed with decreased plasma IGF-I and diminished receptortyrosine kinase signaling. Cancer Prev Res (Phila) 6: 801–810.

Rajpathak SN, Liu Y, Ben-David O, Reddy S, Atzmon G,Crandall J, Barzilai N. 2011. Lifestyle factors of peoplewith exceptional longevity. J Am Geriatr Soc 59: 1509–1512.

Rea IM, McKeown PP, McMaster D, Young IS, Patterson C,Savage MJ, Belton C, Marchegiani F, Olivieri F, Bonafe M,et al. 2004. Paraoxonase polymorphisms PON1 192 and55 and longevity in Italian centenarians and Irish nona-genarians. A pooled analysis. Exp Gerontol 39: 629–635.

Roumie CL, Hung AM, Greevy RA, Grijalva CG, Liu X,Murff HJ, Elasy TA, Griffin MR. 2012. Comparative ef-fectiveness of sulfonylurea and metformin monotherapyon cardiovascular events in type 2 diabetes mellitus: Acohort study. Ann Intern Med 157: 601–610.

Rozing MP, Houwing-Duistermaat JJ, Slagboom PE, Beek-man M, Frolich M, de Craen AJ, Westendorp RG, vanHeemst D. 2010. Familial longevity is associated withdecreased thyroid function. J Clin Endocrinol Metab 95:4979–4984.

Salani B, Maffioli S, Hamoudane M, Parodi A, Ravera S,Passalacqua M, Alama A, Nhiri M, Cordera R, MaggiD. 2012. Caveolin-1 is essential for metformin inhibitoryeffect on IGF1 action in non-small-cell lung cancer cells.FASEB J 26: 788–798.

Samaras TT, Elrick H. 2002. Height, body size, and longev-ity: Is smaller better for the human body? West J Med 176:206–208.

Sanders AE, Wang C, Katz M, Derby CA, Barzilai N, OzeliusL, Lipton RB. 2010. Association of a functional polymor-phism in the cholesteryl ester transfer protein (CETP)gene with memory decline and incidence of dementia.JAMA 303: 150–158.

Sandhu MS, Heald AH, Gibson JM, Cruickshank JK,Dunger DB, Wareham NJ. 2002. Circulating concentra-tions of insulin-like growth factor-I and development ofglucose intolerance: A prospective observational study.Lancet 359: 1740–1745.

Schoenmaker M, de Craen AJ, de Meijer PH, Beekman M,Blauw GJ, Slagboom PE, Westendorp RG. 2006. Evidenceof genetic enrichment for exceptional survival using afamily approach: The Leiden Longevity Study. Eur JHum Genet 14: 79–84.

Sebastiani P, Solovieff N, Dewan AT, Walsh KM, Puca A,Hartley SW, Melista E, Andersen S, Dworkis DA, Wilk



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



JB, et al. 2012. Genetic signatures of exceptional longevityin humans. PLoS ONE 7: e29848.

Sebastiani P, Sun FX, Andersen SL, Lee JH, Wojczynski MK,Sanders JL, Yashin A, Newman AB, Perls TT. 2013. Fam-ilies enriched for exceptional longevity also have in-creased health-span: Findings from the Long Life FamilyStudy. Front Public Health 1: 38.

Seibel SA, Chou KH, Capp E, Spritzer PM, von Eye CorletaH. 2008. Effect of metformin on IGF-1 and IGFBP-1levels in obese patients with polycystic ovary syndrome.Eur J Obstet Gynecol Reprod Biol 138: 122–124.

Smith DL Jr, Elam CF Jr., Mattison JA, Lane MA, Roth GS,Ingram DK, Allison DB. 2010. Metformin supplementa-tion and life span in Fischer-344 rats. J Gerontol A Biol SciMed Sci 65: 468–474.

Suh Y, Atzmon G, Cho MO, Hwang D, Liu B, Leahy DJ,Barzilai N, Cohen P. 2008. Functionally significant insu-lin-like growth factor I receptor mutations in centenari-ans. Proc Natl Acad Sci 105: 3438–3442.

Tabatabaie V, Surks MI. 2013. The aging thyroid. Curr OpinEndocrinol Diabetes Obes 20: 455–459.

Tan Q, Christiansen L, Bathum L, Li S, Kruse TA, Christen-sen K. 2006. Genetic association analysis of human lon-gevity in cohort studies of elderly subjects: An example ofthe PON1 gene in the Danish 1905 birth cohort. Genetics172: 1821–1828.

Tazearslan C, Huang J, Barzilai N, Suh Y. 2011. ImpairedIGF1R signaling in cells expressing longevity-associatedhuman IGF1R alleles. Aging Cell 10: 551–554.

Tosca L, Rame C, Chabrolle C, Tesseraud S, Dupont J. 2010.Metformin decreases IGF1-induced cell proliferation andprotein synthesis through AMP-activated protein kinasein cultured bovine granulosa cells. Reproduction 139:409–418.

Tseng CH. 2012. Diabetes, metformin use, and colon can-cer: A population-based cohort study in Taiwan. Eur JEndocrinol 167: 409–416.

Van Heemst D, Beekman M, Mooijaart SP, Heijmans BT,Brandt BW, Zwaan BJ, Slagboom PE, Westendorp RG.2005. Reduced insulin/IGF-1 signalling and human lon-gevity. Aging Cell 4: 79–85.

Vergani C, Lucchi T, Caloni M, Ceconi I, Calabresi C,Scurati S, Arosio B. 2006. I405V polymorphism ofthe cholesteryl ester transfer protein (CETP) gene inyoung and very old people. Arch Gerontol Geriatr 43:213–221.

Westendorp RG, van Heemst D, Rozing MP, Frolich M,Mooijaart SP, Blauw GJ, Beekman M, Heijmans BT, deCraen AJ, Slagboom PE. 2009. Nonagenarian siblings andtheir offspring display lower risk of mortality and mor-bidity than sporadic nonagenarians: The Leiden longev-ity study. J Am Geriatr Soc 57: 1634–1637.

Whittington HJ, Hall AR, McLaughlin CP, Hausenloy DJ,Yellon DM, Mocanu MM. 2013. Chronic metformin as-sociated cardioprotection against infarction: Not just aglucose lowering phenomenon. Cardiovasc Drugs Ther27: 5–16.



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



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