Disease drivers of aging - Demystifying Medicine › dm17 › m01d... · Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue:Annals Reports Disease

Ann. N.Y. Acad. Sci. ISSN 0077-8923

ANNALS OF THE NEW YORK ACADEMY OF SCIENCESIssue: Annals Reports

Disease drivers of aging

Richard J. Hodes,1 Felipe Sierra,1 Steven N. Austad,2 Elissa Epel,3 Gretchen N. Neigh,4

Kristine M. Erlandson,5 Marissa J. Schafer,6 Nathan K. LeBrasseur,6 Christopher Wiley,7

Judith Campisi,7 Mary E. Sehl,8 Rosario Scalia,9 Satoru Eguchi,9 Balakuntalam S. Kasinath,10

Jeffrey B. Halter,11 Harvey Jay Cohen,12 Wendy Demark-Wahnefried,13 Tim A. Ahles,14

Nir Barzilai,15 Arti Hurria,16 and Peter W. Hunt17

1National Institute on Aging, Bethesda, Maryland. 2Department of Biology, University of Alabama at Birmingham, Birmingham,Alabama. 3Department of Psychiatry, University of California, San Francisco, San Francisco, California. 4VirginiaCommonwealth University, Richmond, Virginia. 5University of Colorado-Anschutz Medical Center, Aurora, Colorado. 6Robertand Arlene Kogod Center on Aging and Department of Physical Medicine and Rehabilitation, Mayo Clinic College ofMedicine, Rochester, Minnesota. 7Buck Institute for Research on Aging, Novato, California. 8David Geffen School ofMedicine, University of California, Los Angeles, Los Angeles, California. 9Department of Physiology and CardiovascularResearch Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania. 10Barshop Institute forLongevity and Aging Studies, University of Texas Health Science Center, South Texas Veterans Health Care System, SanAntonio, Texas. 11Division of Geriatric and Palliative Medicine, University of Michigan, Ann Arbor, Michigan. 12Duke UniversitySchool of Medicine, Durham, North Carolina. 13University of Alabama at Birmingham Comprehensive Cancer Center,Birmingham, Alabama. 14Memorial Sloan Kettering Cancer Center, New York, New York. 15Institute for Aging Research, AlbertEinstein College of Medicine, New York, New York. 16City of Hope National Medical Center, Duarte, California. 17University ofCalifornia, San Francisco, School of Medicine, San Francisco, California

Address for correspondence: [email protected]

It has long been known that aging, at both the cellular and organismal levels, contributes to the development andprogression of the pathology of many chronic diseases. However, much less research has examined the inverserelationship—the contribution of chronic diseases and their treatments to the progression of aging-related pheno-types. Here, we discuss the impact of three chronic diseases (cancer, HIV/AIDS, and diabetes) and their treatmentson aging, putative mechanisms by which these effects are mediated, and the open questions and future researchdirections required to understand the relationships between these diseases and aging.

Keywords: disease; aging; pathology; chronic; prevention; age-related; HIV; diabetes; cancer

Introduction

The geroscience hypothesis, that aging is the majormodifiable risk factor for most chronic diseases,is currently well accepted and it is being tested inmultiple models and systems, ranging from basicbiology in a variety of organisms to preclinical andclinical studies. Aging has been recognized for yearsas a major risk factor for most chronic diseases thataffect the aged population. However, it has tradi-tionally been overlooked as a nonmodifiable riskfactor, and thus neglected in most of our approachesto medicine. This has changed recently becauseof the recognition, among basic biology of agingresearchers, of a limited number of pillars that seem

to be the main drivers of the aging process. Identifi-cation of these pillars was made possible by a multi-pronged approach based on the now classical tenetsof aging biology: caloric restriction, cell senescence,and free radicals. While the initial theories and con-cepts driving each of these fields have been subjectedto modifications and redefinitions, research basedon these tenets has allowed researchers to identifythe major drivers of the process. This in turn hasled to the beginnings of efforts aimed at translat-ing the findings through the use of pharmacologicalapproaches aimed at one or more of the pillars ofaging, with the hope that, by addressing these funda-mental drivers, a positive impact might be achieved

doi: 10.1111/nyas.13299

45Ann. N.Y. Acad. Sci. 1386 (2016) 45–68 C⃝ 2016 New York Academy of Sciences.

Disease drivers of aging Hodes et al.

in combating not one but multiple chronic diseasesin parallel.

On the other hand, it is well established that agingand disease susceptibility are highly variable amongindividuals within the human population, mostlikely due to variations in the well-known inter-actions between genes and environment. Againstthis background, a major environmental variableknown epidemiologically to affect the “rate of aging”(colloquially understood, as there is no agreed-upon definition or measure for the rate of aging)is exposure to early serious disease. It has been wellestablished, at the epidemiological level, that earlyexposure to severe diseases and/or their treatmentsleads to an acceleration of aging, as defined by anincreased and premature risk of developing diseasesand conditions that are associated with increasedage. In order to narrow the discussion, in the SecondGeroscience Summit, held on April 13–14, 2016 inNew York, New York, we focused on three examples:cancer, HIV/AIDS, and diabetes. This was drivensimply by the need to limit the scope of the discus-sions, but it is expected that the issues raised willapply, with modifications, to all or most diseasesthat, while curable, nevertheless leave sequelae thatare likely to affect later increased susceptibility toage-related diseases and conditions.

That serious diseases and/or their treatments leadto an acceleration of disease susceptibility later in lifeis well established at the epidemiological level. Thegoal of the summit was to dig further and try toassess possible molecular and cellular mechanismsthat might be responsible for the epidemiologicalobservations. A specific emphasis was placed onlinks between diseases and/or treatment and themajor pillars of aging, with the assumption that ifthese early life events affect some of the same pil-lars that have been associated with aging, then thisshould be a good place to start addressing the rela-tionship between the two.

Geroscience as a multidisciplinaryapproach to understanding aging

Richard J. HodesThe extramural program of the National Instituteon Aging (NIA) at the National Institutes of Health(NIH) is organized around four divisions, and eachis poised to make unique and substantive contri-butions to the field of geroscience. The Division ofAging Biology is the lead for geroscience at the NIA,

Figure 1. The pillars of geroscience. Adapted from Refs. 1and 2.

and its focus is on the basic biochemical, genetic,and physiological mechanisms underlying the pro-cess of aging and age-related changes in humansand in animal models of human aging. Geroscienceis a natural extension of this work. The Division ofNeuroscience focuses on the dementias of old age, aswell as understanding the processes associated withthe normally aging brain. The basic science researchfunded by this division intersects with gerosciencein the areas of biologic mechanisms of disease (e.g.,dementias) and age-related changes in the brainthat lead to increased disease risk. The Division ofBehavioral and Social Research explores aging atthe individual and the societal level—and researchin areas like the biological mediators of social stres-sors provides a connection to geroscience. Last, theNIA’s Division of Geriatrics and Clinical Gerontol-ogy supports research on health and disease in theaged and research on aging over the human life span;its focus on aging-related diseases offers a close linkto geroscience.

Similar connections can be made throughout theNIH. The NIH comprises 27 different institutes andcenters (ICs), and nearly all of them investigate atleast some diseases and conditions for which agingis a risk factor. Aging-related changes affect bodilyfunctions at every level, from cellular metabolismand inflammatory responses to proteostasis andepigenetic modifications. These changes thatoccur with age have been termed the “pillars ofgeroscience” (Fig. 1). It is the intersection of theseprocesses with the mechanisms underlying manycritical aging-related diseases that drives a commoninterest for NIA and the NIH ICs that supportresearch on these diseases.

The need to raise awareness of the role ofaging biology in disease development prompted

46 Ann. N.Y. Acad. Sci. 1386 (2016) 45–68 C⃝ 2016 New York Academy of Sciences.

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Table 1. Medical procedures needed to enable continu-ing ability to perform the normal activities of daily living(various sources)

Procedure Annual number in United States (2014)

Cataract surgeries 3,000,000Knee replacements 720,000Hip replacements 330,000

the NIA—along with 20 other ICs at the NIH—toform a geroscience interest group (GSIG). The GSIGhelped to organize an initial Geroscience Summit in2013, which resulted in several activities, includingpapers, a book, and some multi-institute fundingopportunity announcements. Continued NIH andextramural community interest in the field led tothe organization of a second summit, reported here,in April 2016.

Over the past several years, a number of sci-ence advances illustrate these connections and,importantly, the unique role that aging can playin disease development, as well as in responses todisease interventions. One of the most significantNIA-supported findings of this type was the resultfrom the Diabetes Prevention Program studies—ledby the National Institute of Diabetes and Digestiveand Kidney Diseases—that showed an especiallyprofound effect of a lifestyle intervention inpreventing diabetes in individuals over 60 years,relative to the effect of the same interventionin younger participants.3 Basic science studieshave also demonstrated the potentially life-savingimportance of preclinical testing of therapies inolder animals. A 2013 study by Bouchlaka et al.4

found that one systemic cancer immunotherapystrategy was 100% lethal to older mice after 48 h,yet all of the younger animals tested survived andwere in fact helped by the therapy.

The geroscience pillars will continue to informthis work as more of it moves from the benchthrough translational research applications to clin-ical trials. As just one example, it has been reportedthat removal of senescent cells from an aging mousethrough an innovative genetic strategy results inenhanced structure and function of muscle andother tissue.5 These and other recent findings inmodel systems provide a basis for translation intoclinical studies—and meetings like the summit aredesigned to catalyze these discoveries.

Disease drivers of aging as a topicof geroscience

Felipe SierraAging is recognized as the major risk factor formost chronic diseases and disabilities. However,there is still a widespread perception that aging isimmutable, and thus both research and clinical trialsoften focus on curing or preventing specific diseasesrather than addressing the core: aging itself. Againstthis background, researchers have made impressiveprogress in the last few decades in understanding thegenetics, biology, and physiology of aging, using averitable zoo of laboratory animals to model humanaging.6 This has made possible the emergence of thefield of geroscience, the intersection between basicaging biology and disease.7 The aims of geroscienceare to understand the molecular and cellular basis ofhow aging enables disease and to exploit that knowl-edge. Indeed, the geroscience hypothesis states that,by reducing the rate of aging, it should be possibleto delay or slow down the appearance and progres-sion of not one but most age-related chronic ail-ments, all at once.8 This includes life-threateningdiseases, such as cancer, vascular disease, diabetes,and many others, as well as chronic diseases (arthri-tis, osteoporosis, mild cognitive impairment) andconditions (frailty, loss of resilience, fatiguability)that, while not life threatening themselves, never-theless severely diminish quality of life.

The trans-NIH GSIG was formed with the goalof promoting awareness and discussion on theseissues. A major activity of the GSIG has been thesummits. The first Geroscience Summit, in October2013, focused on exploring the molecular and cellu-lar mechanisms underlying aging as the major riskfactor for all chronic diseases. Seven major pillars ofaging were identified at that time,9 and the door wasleft open for additional pillars not yet identified. Onesuch underexplored pillar could be the appearanceof early major diseases and their treatment, whichhas been shown in epidemiological studies to lead topremature or accelerated appearance of age-specifictraits, including chronic morbidity. As a result, a sec-ond Geroscience Summit was co-organized by theGSIG in conjunction with the American Federationfor Aging Research, the Genetics Society of Amer-ica, and the New York Academy of Sciences. Themeeting was held in April 2016, and it was decidedto address the question: What are the molecular and



cellular mechanisms that might explain why somediseases accelerate the aging process, leading to pre-mature appearance of age-related diseases and con-ditions? The fact that there is such an accelerationhas been demonstrated extensively in the literature,and therefore further discussion of epidemiologi-cal data confirming these results was discouraged.Rather, as in the first summit, the emphasis wason molecular and cellular events occurring as afunction of the disease or its treatment that mightimpinge on the rate of functional deterioration thatoccurs during normal aging. In an effort to nar-row the discussions, three diseases were chosen:HIV/AIDS, diabetes, and cancer. Both the effectsof the diseases themselves and the effects of theirtreatments were discussed by panelists in three sep-arate sessions, as well as a roundtable discussionat the end, focused on identifying open researchquestions that need to be addressed to advance ourunderstanding of how these diseases might affectthe aging process.

While the summit focused separately on the threechosen diseases, it is acknowledged that people ofadvanced age are rarely affected by a single chronicdisease; rather, they are often afflicted by multi-ple comorbidities and conditions that limit theirhealth. However, during the discussions, the focuswas primarily on early appearance of the diseasesin relatively young people. In those cases, cancer,HIV/AIDS, and diabetes are often found to occuralone, and the initial disease is often addressed vig-orously. This has led to important increases in sur-vival and extended life span in affected individuals.However, comorbidities are observed later, as thepatients age, and the summit addressed the down-stream consequences, in relation to decreased healthspan—the portion of life spent in good health.

The geroscience hypothesis: what do weknow?

Steven N. AustadThe progressive deterioration of physiological func-tion over time, aging occurs even in the absenceof disease, as shown by the steady decline in per-formance even of the world’s best master athletes asthey grow older. However, aging is intimately associ-ated with a wide range of diseases—virtually all thefatal diseases of modern life—because it increasesvulnerability to, and compromises the ability torecover from, diseases. Whether diseases themselves

can accelerate aging is a hypothesis many researchersare currently considering.

It is important to remember that nonfatal mal-adies of aging, such as increased joint pain, loss ofvision and hearing, and muscle weakness, shouldnot be neglected, as they have become particu-larly important in recent times. As successful asthe biomedical community has become at delayingdeath, shown by the steady rise of life expectancyfor well over a century, it has not been successfulat delaying aging itself. Consequently, the numberof people needing joint replacement due to chronicpain, cataract surgery due to low vision, or assistancein the simple activities of daily living has steadilyrisen as well (Table 1). These chronic fatal and non-fatal maladies of later life have now become thenumber one threat to human health globally.

In the past two decades, the aging research com-munity has been successful at discovering methodsto extend the life of model laboratory animals. Thesemethods include genetic, dietary, and pharmaceu-tical interventions. This research has revealed keyplayers, such as insulin/IGF and mTOR signaling,in complex, interconnected molecular networks thatappear to underlie organismal longevity. However,despite these successes, at least three critical ques-tions remain unanswered.

First, do life-extending interventions extendhealth or do they simply delay death? With refer-ence to their ultimate translation into human ther-apies, this is perhaps the most important unan-swered question. Recently, assessment of age-relatedhealth trajectories has become a major focus of lab-oratory longevity studies. Certainly, extending theunhealthy period of life near its end is not a goalworth pursuing.

Second, will life-extending interventions beeffective outside of the laboratory environment?Researchers work very hard to protect their experi-mental animals from infectious diseases, poor diets,and unpredictable environmental events. Will life—and more importantly health—also be extended inpathogen-rich, unpredictable environments, wheresubstandard diets may be the norm? Some inter-ventions, such as dietary restriction, appear tocompromise resistance to at least some infectiousdiseases,10,11 so that is a substantial consideration inthe real world.

Third, of course, is whether the effects of interven-tions that were observed in short-lived laboratory



species will translate into similar effects in longer-lived species, such as humans. It is well known thatonly a fraction of interventions that successfullytreat cancer in mice have turned out to be therapeu-tically viable in humans.12 So far, not even a fractionof Alzheimer’s disease (AD) therapies have trans-lated from success in mice to success in humans.13

There is no way to determine whether this willbe true for known interventions in mouse agingwithout performing the human trials. Such trials,involving older people as participants, would notneed to be excessively lengthy to detect whetherhealth is extended. Multiple drug candidates havealready been identified. It is time for the first clinicaltrial of putative senescence-retarding therapies.

The complex bidirectional relationshipsbetween chronic disease and telomereattrition

Elissa EpelTelomeres are a window into one type of aging—replicative senescence, the inability of mitotic cellsto continue to divide and, thus, for tissue to replen-ish. The most common measure of telomere lengthin human studies is the average telomere lengthin blood, across all immune cells. Telomere short-ness is an early risk factor for immune senescence.When telomeres reach a critical shortness, the cellenters either senescence or apoptosis. The intra-cellular enzyme telomerase can promote telomerelengthening, preventing the age-related shorteningthat comes with cell division.

Telomeres predict disease in humansDamage to telomeres or an inability to rebuildtelomere length after cell division is thought to be avery common pathway to cell senescence in humans,partly because we are so long lived. In lower species,telomeres may be a much less important pathwayto senescence. For example, rodents both start outwith very long telomeres and live shorter lives. In thiscase, telomere attrition is only important in extremeexamples (knockouts and in subsequent generationswhen telomeres become very short).

Telomeres in humans are helpful as a marker—they are easy to measure in population-based stud-ies and are predictive of early onset of diseases ofaging, as shown by many meta-analyses. Telomerelength is also an easy-to-get measure that signalsthat other likely aspects of cell aging may be present.

Short telomeres are bidirectionally related to otheraspects of aging biology. For example, dysfunctionaltelomeres impair mitochondria and lead to systemicinflammation. Telomeres also play a direct mecha-nistic role in aging, as shown by Mendelian random-ization studies (e.g., Ref. 14).

Disease processes may shorten telomeresThere is now a robust literature showing that telom-ere shortness precedes the onset of cardiovascu-lar disease and diabetes. Early telomere attritioncreates risk for early diseases of aging. However,once one has a chronic disease, many aspects of thedisease process can promote accelerated telomereattrition. While there are a myriad of biochem-ical alterations in each disease, a common triadunderlying many diseases of aging is oxidativestress, inflammation, and hyperglycemia/insulinresistance. Diabetes offers a clear example of how thedisease process further shortens telomeres.15 Onceone has diabetes, the impaired ! cell function andresulting higher levels of these biochemical stressorscan further shorten telomeres.

This is also apparently the case for major psychi-atric diseases. The presence of psychiatric disease isassociated with shorter telomeres, particularly formajor depression and anxiety disorders. There aredose–response relationships such that the longer theduration of the depression, the shorter the telomerelength.16 It may also be that the short telomeres alsopreceded the onset of the condition, and longitu-dinal studies are needed to determine the strengthof causal directions. Given the high comorbidity ofmedical and psychiatric conditions, it is importantto take into consideration that the common condi-tion of depression may alter aging biology, not justthe physical disease condition.

Disease treatments modulate telomereattritionTreatments for diseases may further affect the rate oftelomere attrition, either speeding it up or slowing itdown. Few studies have directly examined the effectsof medications. Statins and possibly metforminmay prevent telomere attrition.17 In contrast, highlyactive antiretroviral therapy (ART) in HIV appearsto accelerate telomere attrition. Chemotherapy canwork through telomere damage of both cancerouscells and healthy cells.18

While cell aging predicts disease, once one has dis-ease, there is undoubtedly a clouded and complex



picture, where both disease processes and aspectsof treatment can further affect telomere stabilityand repair, and thus rate of attrition over time.There is a tremendous amount that could be eas-ily learned by incorporating assessments of cellu-lar aging, such as telomere length, into treatmentstudies.

The bidirectional relationship betweenstress and HIV

Gretchen N. NeighIndividuals living with HIV are subject to a highstressor burden. This burden includes the influenceof external stressors, such as financial burden andstigma, as well as the burden of the internal stres-sors of viral presence and antiretroviral medication.Evidence of the burden of these stressors is evidentin the increased incidence of stress-related disor-ders among individuals living with HIV, such asdepression and posttraumatic stress disorder.19 Fur-thermore, comorbidity of affective disorders withHIV affects overall longevity, as demonstrated bythe report that women living with depression andHIV have higher mortality than euthymic womenliving with HIV.20

In order to understand how stressors and HIVmay interact, it is important to visualize the rela-tionship between stress and stressors. An organ-ism’s response to a stressor is the physiologicalstate of stress, and stress is designed to return theorganism to homeostasis. Similar to a rubber bandbeing stretched, the relationship between stressorsand stress is initially completely predictable andreversible. The force (stressor) is applied, and thestress response of the organism returns the system tohomeostasis—the relationship is elastic or resilient.However, if the stressors are too great, the elasticityof the system begins to be compromised such thatthe force applied does not predictably generate thesame response and the return to homeostasis may beincomplete or require shifts in function—the rela-tionship is adaptable. If stressors are applied to anextreme point for a prolonged period of time, orif a genetic or environmental predisposition exists,then the response generated becomes maladaptive.In the case of HIV, it is likely that the combined stres-sor burden shifts the relationship between stressorsand the stress response to the point that a resilientresponse is less likely and adaptation is a more real-istic goal for stress management.

The stress response can be managed at boththe psychosocial and biological levels. Regardless ofwhether the origin of the stressor is psychosocial orbiological, the initiated processes in the organismare virtually identical—that is, the hypothalamic–pituitary–adrenal (HPA) axis that facilitates thestress response does not differentiate between typesof stressors. At the psychosocial level, interventionsthat reduce the impact of stressors, such as stigma,loss, or financial strain, can in part minimize theimpact of HIV on the stress response system by pre-venting the initiation of a stress response. The bio-logical response to stressors is also affected by HIV.This level of modulation has two primary points ofintervention or titration: magnitude and duration.In relation to magnitude, both the cumulative bur-den of psychosocial stressors21 and the impact ofviral proteins22 have been shown to alter the stressresponse.

Although the impact of HIV on the stressresponse is multifaceted, there are also multiplepoints of intervention. Psychosocial interventionsare useful and important in the context of HIV.However, it is valuable to note that the stress-response system of individuals living with HIV isdifferent than those without the disease, and it maybe necessary to consider biological support for theHPA axis in order to allow the patient to reap the fullbenefits of a psychosocial intervention. In addition,it is vital to recognize that, while ART is effectivein reducing viral loads and restoring CD4 counts,these drugs are not without impact, and the influ-ence of these compounds on P450 and other aspectsof the stress response system can render patientsmore susceptible to the impact of stressors.23 Finally,given the ubiquitous nature of stress hormones, tar-geted end-organ interventions for the systems mostaffected in an individual demonstrating the reper-cussions of a cumulative stressor burden may be themost effective method of intervention for individu-als aging with HIV.

From wasting to obesity: HIVand its therapy in aging

Kristine M. ErlandsonSome of the earliest manifestations of AIDS werethe profound wasting observed with uncontrolledHIV infection, before the introduction of effectiveART. Similar to that of cancer cachexia, the wast-ing was multifactorial and due in part to nutritional



deficiencies, increased resting energy expenditure,infections, cancers, and high levels of inflammation.The result was a significant loss in both muscle andfat. With the advent of effective ART, these weightchanges could be partially reversed; however, theimpact of HIV and ART on muscle and fat was farfrom over. Men with a history of wasting gained lessweight over time and remained an average of nearly10 kg less than men without a history of wasting.24

Importantly, this low muscle mass has been associ-ated with increased mortality.25 Both ART and HIVwere found to have toxic effects on the muscle, withmany of the older nucleoside reverse transcriptaseinhibitor (NRTI) therapies later implicated in mito-chondrial toxicity.26 HIV-infected adults also havebeen shown to have gene expression patterns con-sistent with fibrosis and collagen deposition27 andto have greater fatty infiltration of the muscle anddecreased strength with aging compared with HIV-uninfected controls.28,28a

The early era of ART was quickly complicatedby lipodystrophy, a constellation of changes in fatdistribution, including both lipoatrophy, a loss ofsubcutaneous fat of the face and extremities, andlipohypertrophy, a gain in visceral, truncal, or dor-socervical fat. Older NRTI therapies have been mostimplicated in lipoatrophy, but there is evidencethat all ART can contribute to lipohypertrophy.Even the newest ART regimens are associated withmarked gains in fat, with some studies showing upto a 30% increase in visceral fat over just the first2 years of treatment.29 The severity of lipodystrophycan range from very mild to quite severe and stig-matizing. Certain ARTs contribute to a variety ofadditional pathologies in fat that can become morepronounced in the setting of lipodystrophy, includ-ing mitochondrial toxicity and disruption inadipocyte differentiation. Additionally, lipolysis thatoccurs in lipoatrophy is associated with an accu-mulation of free fatty acids, which ultimately maybe deposited in visceral fat, muscle, or the liver.More recent data suggest that adipose tissue mayactually serve as a reservoir for HIV virus, allowingfor viral replication and further inflammation andsubsequent adipose tissue dysfunction (reviewed inRefs. 30 and 30a). The favorable weight changesamong AIDS patients initiating ART were initiallyattributed to a return to health following a periodof profound weight loss. Although the majority ofHIV-infected adults now start on ART at much ear-

lier stages, well before wasting, this weight gainhas continued to occur. Thus, the problem ofobesity, often overlapping with lipodystrophy, isnow quite common. Regardless of the cause, theconsequences of both obesity and HIV- or ART-attributed body fat changes are additive and result inincreased insulin resistance, immune activation, andinflammation.

Changes in body composition resulting from HIVinfection and complications of ART mimic those ofnormal aging, with facial atrophy, a loss of skele-tal muscle mass, and accumulation of visceral andother ectopic fat. Furthermore, the combinationof both low muscle mass and increased fat con-tent (referred to as sarcopenic obesity) likely hasa synergistic effect in HIV.25 These body composi-tion changes are associated with changes in mito-chondrial function and insulin resistance and bothcontribute to and are worsened by chronic inflam-mation. While newer ART will eliminate or min-imize some of the insults seen early in the AIDScrisis, these changes contribute to comorbid diseasedevelopment. Not unexpectedly, the result is whatappears to be an earlier occurrence or worsenedseverity of many diseases of aging. Indeed, severalcohorts have shown an earlier or more profoundmanifestation of many age-associated conditions,such as frailty, falls, fractures, cardiovascular disease,diabetes, cancers, and neurocognitive impairment,in HIV-infected adults.

With the body composition changes that manyolder, HIV-infected adults have experienced, the riskfor age-associated diseases is often markedly under-estimated. Prevention and treatment strategies fordisease progression must target multiple pathways.Although we may not be able to eliminate the dam-age done with current ART, interventions targeted atmuscle and fat have the potential to result in markedimprovements in both the health span and lifespan.

The gut barrier, microbiome, and healthin HIV and aging

Peter W. HuntCommon features of aging in both animal mod-els and humans—including models of accentuatedaging, like HIV infection—include breakdown ingut barrier function and dysbiosis of the gut micro-biome. Indeed, in the very earliest stages of HIVinfection, gut epithelial barrier function is impaired



by breakdown of tight junctions between epithelialcells, increased epithelial cell apoptosis, and loss ofmucosal immunity. These defects allow for translo-cation of microbial products into the systemiccirculation and a chronic inflammatory state.152

Markers of gut epithelial barrier dysfunction inHIV strongly predict increased mortality, even aftersuppression of viral replication is achieved withART,153 suggesting that these defects might plausiblyplay a role in driving disease. Similarly, gut barrierdefects are commonly observed with aging in sev-eral different species, from Drosophila to baboonsand humans.154–156 While the specific mechanisticpathways that drive these gut barrier defects maydiffer between species and model system, the resul-tant systemic inflammatory state from microbialtranslocation may well contribute to several end-organ complications and an accentuated aging phe-notype. Dysbiosis of the gut microbiome also occursin both HIV infection and aging and may contributeto systemic pathology, not simply through increasedmicrobial translocation, but also via the pathologicmetabolic products that they produce. Some of theseproducts, such as those of the kynurenine path-way of tryptophan catabolism, may have a multi-tude of deleterious effects on the immune system,the nervous system, and even mental health.157,158

These mechanistic similarities between HIV andaging provide multiple potential therapeutic tar-gets to improve the health span in each setting.That said, the degree to which dysbiosis and micro-bial translocation are causes or consequences of theinflammatory state in both HIV infection and agingremains unclear. While animal model data suggesta potential causal role of dysbiosis and microbialtranslocation in contributing to multimorbidity andmortality,154 targeted clinical trials are needed inhumans to prove causality in both the HIV andaging fields. It also needs to be recognized that, justas the specific underlying mechanisms leading todysbiosis and microbial translocation in HIV andaging may differ, the optimal strategies for therapeu-tic interventions may also differ. Nevertheless, rec-ognizing the mechanistic similarities between HIVand aging may help prioritize interventional tar-gets to pursue and accelerate our understanding ofeach condition as these research agendas proceed inparallel.

GDF11 and myostatin: new evidencefor roles in aging

Marissa J. Schafer and Nathan K. LeBrasseurA central endeavor in geroscience research is to iden-tify circulating mediators of biological aging. If suchfactors exist, harnessing or blocking their action maytranslate to enormous therapeutic potential. Untilrecently, growth differentiation factor 11 (GDF11)was believed to be a promising prorejuvenative pro-tein that declines in the bloodstream throughoutchronological aging. Therapeutic replenishment toyouthful levels was demonstrated to restore regener-ative capacity in muscle, heart, and brain (reviewedin Ref. 31).

GDF11 is remarkably homologous to myostatin(MSTN, also known as GDF8), differing in aminoacid sequence within their mature domains byonly 11 residues. GDF11 and MSTN also sharecanonical TGF-! posttranslational processing andsignaling, through binding to the activin type I orII receptors and subsequent activation of SMAD. Incontrast to GDF11’s purported progrowth effects,MSTN is a potent negative growth regulator, withblockade or loss of function resulting in skeletalmuscle hypertrophy and hyperplasia. Accordingly,MSTN inhibition is a potential strategy to improvemuscle-wasting conditions, including sarcopenia,cachexia, and frailty (reviewed in Ref. 32). Thus,a central question plagues the field: how canGDF11 and MSTN, doppelgangers in structure andsignaling, exert antithetical functional effects?

New discoveries have begun to shed light onthis issue, which include several studies challengingGDF11’s antiaging, progrowth influence (reviewedin Refs. 33 and 34). A critical emerging experi-mental consideration is the requirement of detec-tion methods that are able to resolve GDF11 fromMSTN. The aptamer-based profiling platform thatwas employed in the studies implicating GDF11in rejuvenative processes was unable to distin-guish between GDF11 and MSTN. Similarly, cross-reactive antibody-based methods have been reliedupon. The realization that these assays were insuffi-ciently discerning has underscored the need for newdetection methods (reviewed in Ref. 33). The mostrobust approaches are anticipated to leverage massspectrometry (MS) for quantification of GDF11-and MSTN-based amino sequence differences.34a



Moreover, methods integrating both immunopre-cipitation and MS will be useful for determin-ing the physiological contexts in which variousforms of GDF11 and MSTN (latent vs. mature)travel and their associations with regulatory pro-teins, such as follistatin, follistatin-like 3, and GDF-associated serum proteins (reviewed in Ref. 35).Indeed, these proteins likely play important context-dependent inhibitory or chaperone roles. Whetherand how these complexes contribute to differingtissue targeting or activation of cognate recep-tors by GDF11 and MSTN, or changes in variousstates of health, aging, and disease, remain to beseen.

Explorations of circulatory dynamics mayilluminate unknown local versus systemic activities.MSTN is expressed predominantly in skeletalmuscle, and GDF11 is expressed more ubiquitously.Temporal considerations also appear to conveyimportant functional differences. Mutation andexpression patterns suggest that GDF11 is develop-mentally requisite, particularly for axial patterning,while MSTN wields antigrowth effects throughoutdevelopment and adulthood. Furthermore, inhumans, limited studies have interrogated asso-ciations between circulating GDF11 and MSTNabundance and clinically important health out-comes (e.g., physical, cardiovascular, or cognitivefunction). Such data will help substantiate the roleof these proteins in aging and, ultimately, theirtherapeutic potential.

The questions that remain are reminiscent of agame of clue. Which protein is it? In which tissue didit originate, and in which tissue is it exerting influ-ence? Through which mechanisms (e.g., canoni-cal activin receptor signaling, bound to regulatoryproteins) is it acting? What are the GDF11- andMSTN-specific outcomes, and are these functionsconserved in rodents and humans? Recent contro-versy emphasizes the need to utilize highly precisemethods if we are to solve this mystery.

Mitochondrial dysfunction–associatedsenescence as a promoter of lipoatrophyin response to antiretroviral therapy

Christopher WileyThe advent of ARTs has held great promise forthe treatment of HIV. These therapies lower viralload, preventing development of AIDS and, ulti-mately, delaying death. As a result of ART, individu-

als now regularly live decades after infection withoutdeveloping life-threatening complications. Unfor-tunately, while treated individuals enjoy extendedlife spans relative to what they might without ART,patients now appear in the clinic with conditionsthat resemble premature aging—including cogni-tive impairment, cardiovascular disease, diabetes,osteoporosis, and lipodystrophy.36 The net effect ofthese various maladies is a reduced quality of lifecoupled to a shortened life span relative to unin-fected individuals. These comorbidities suggest thatone or more basic processes of aging are activatedby either infection with HIV, the ART treatmentsthat keep HIV in check, or both. While differentiat-ing between these possibilities is challenging (HIV-infected patients do not live long without ART, whileHIV-uninfected people do not normally receiveART), murine and tissue culture models of ARTtreatment now suggest that these therapeutics acti-vate one or more basic proaging processes.

What basic biological processes might promoteaging in response to ART? Many ART drugs, includ-ing the NRTIs, such as zidovudine and stavudine,37

and non-nucleoside reverse transcriptase inhibitors,such as efavirenz, can interfere with normal mito-chondrial function, and thus many have nonvi-ral off-target effects. NRTIs are most commonlyassociated with mitochondrial dysfunction becausethey can inhibit mitochondrial DNA polymerase "(POLG), resulting in mitochondrial DNA depletion.Similarly, efavirenz inhibits complex I on the mito-chondrial electron transport chain, lowering cellularenergy (ATP) levels and increasing oxidative stress.38

Thus, many ART drugs can induce a state of mito-chondrial dysfunction in otherwise healthy cells.

How might ART-induced mitochondrial dys-function drive age-related conditions? Both mito-chondrial DNA depletion and inhibition of complexI induce cellular senescence, a state of essentiallypermanent mitotic arrest.39 This mitochondrialdysfunction–associated senescence (MiDAS) candrive age-related conditions via two mechanisms.First, the cellular arrest prevents senescent pro-genitor cells from repopulating a tissue. Second,MiDAS is accompanied by a senescence-associatedsecretory phenotype (SASP) that is distinct fromother known inducers of cellular senescence. TheMiDAS SASP consists of a melange of biologicallyactive molecules that can have potent effectson local tissues. For example, the MiDAS SASP



inhibits the differentiation of adipocytes. Indeed,POLG mutant mice—which display profoundlipoatrophy—accumulate senescent cells at a rapidrate.39 Lipoatrophy is also a common consequenceof ART, and senescent cells appear in adiposetissue of patients that receive some NRTIs.2 Thus,senescent cells are somewhat of a “smoking gun” asan etiological agent for ART-induced lipoatrophyand possibly other age-related phenotypes.

Are senescent cells truly causal for age-relatedconditions associated with ART? Thus far, the evi-dence is largely correlative, with senescent cellsappearing at the right places and times in condi-tions like ART-associated lipoatrophy. Fortunately,recent murine models in which senescent cells areselectively eliminated have shown that senescentcells indeed promote features of aging.40 Thesetypes of models hold promise both for determiningwhether senescent cells promote age-related condi-tions associated with ART and as a potential basisfor novel therapeutic interventions aimed at elimi-nating senescent cells.

DNA methylation age is accelerated beforeAIDS-related non-Hodgkin lymphomadiagnosis

Mary E. SehlDiffuse large B cell lymphoma is the most commonaggressive non-Hodgkin lymphoma in the UnitedStates, and its major risk factors include advancingage and immunosuppression. Markers of chronicB cell activation are elevated in both normal agingand HIV infection and are associated with risk ofdeveloping AIDS-related non-Hodgkin lymphoma(AIDS-NHL).41 Aging and HIV infection lead toaccumulation of immunosenecent cells and alteredmethylation of polycomb group target (PCGT)genes, which are involved in stem cell self-renewal,and whose methylation is aberrant in dysplasia andcancer.42 Acceleration of age-related methylationpatterns involving CpGs from the PCGT pathwayhas been recently demonstrated in the setting ofHIV-1 infection.43 The goal of our work is to charac-terize epigenetic patterns that are involved in aging,HIV infection, and lymphomagenesis.

The epigenetic clock, derived from 8000 sam-ples from 82 Illumina DNA methylation (DNAm)and array data sets from 51 healthy tissues and celltypes, allows one to estimate DNAm age of tissues,

using methylation levels at 353 CpGs from path-ways involved in cell apoptosis and survival, self-renewal, and tissue development.44 DNAm age ishighly correlated with chronologic age across tis-sues and species, correlates with cell passage num-ber, is close to zero for embryonic stem cells andiPSCs, is highly heritable, and is applicable acrossspecies, and age-acceleration is seen in some can-cer tissues.44 An online epigenetic age calculator isavailable for calculation of DNAm age on the basisof data measured using the Illumina Infinium plat-form (450K or 27K data) (https://labs.genetics.ucla.edu/horvath/dnadamage/).

In our study, we utilize peripheral bloodmononuclear cells previously collected from partici-pants at the Los Angeles site of the Multicenter AIDSCohort Study (MACS). We analyze global methyla-tion data from men who later developed AIDS-NHLat two time points (1–4 years and >4 years beforediagnosis) and compare it to that of HIV-infectedcontrols matched on CD4+ T cell count and HIV–

controls. We study participants from a broad agerange (early 20s to late 50s). Lymphoma subtypes inour study include Burkitt’s lymphoma, diffuse largeB cell lymphoma, and immunoblastic lymphoma.

From bisulfite sequencing experiments using theIllumina Infinium 450K platform, we estimateDNAm age of peripheral blood mononuclear cellsfrom MACS study participants using the epige-netic clock method. Preliminary results of our studyconfirm earlier studies showing that DNAm age isstrongly correlated with chronologic age and thatHIV-infection is associated with age accelerationin the epigenetic clock. Our laboratory is activelyexamining age-acceleration differences in samplesfrom individuals who do and do not later developlymphoma and comparing the degree of acceler-ation from visits closer to lymphoma diagnosis(1–4 years before) versus earlier time points(>4 years before).

Preliminary results confirm that DNAm age isaccelerated in peripheral blood mononuclear cellsin the setting of HIV infection and suggest thatDNAm age acceleration is increased in the yearsbefore AIDS-NHL diagnosis. We are well poised inour laboratory to further examine the relationshipbetween global methylation changes and elevationsin chronic inflammatory markers that occur beforeAIDS-NHL diagnosis.


https://labs.genetics.ucla.edu/horvath/dnadamage/

https://labs.genetics.ucla.edu/horvath/dnadamage/


Which mechanisms do or do not driveaging in diabetics?

Nir BarzilaiDiabetes is considered a model for accelerated aging.It is imperative, though, to seek the pathology thatcommonly exists in the elderly and then deter-mine if it is accelerated with diabetes. For exam-ple, although macrovascular diseases are commonin the elderly, recent study suggests that cardiovas-cular disease mortality and all mortality are notaccelerated by diabetes; in fact, they are deceler-ated in elderly over the age of 75 years who havediabetes.127 Severe microvascular complications ofdiabetes—proliferative retinopathy, peripheral andautonomic neuropathy, and end stage (Kimelstein-Wilson kidney) nephropathy—do not appear in thenondiabetic elderly and have been demonstrated tobe mainly the consequence of hyperglycemia ratherthan aging. Insulin resistance is a hallmark of agingand type 2 diabetes mellitus (T2DM). Yet insulinresistance is also a stress response and is part of adap-tive/protective response to deal with extra nutri-ents. In fact, in animal models there is no central-ity to insulin sensitivity in predicting life span.128

There are numerous models of insulin resistancemodels that live significantly longer; treatment withrapamycin is an example. There are also numer-ous models with enhanced insulin sensitivity withnormal or shorter life span; protein tyrosine phos-phatase, non-receptor type 1 (Ptpn1) knockout miceis an example of an insulin-sensitive model with asignificantly decreased life span.

The progress in aging has been accelerated bystudying models that have extended health andlife spans. Interestingly, studies have determinedthat commonly used antidiabetic drugs, such asmetformin129 and acarbose,130 may extend healthspan and life span in animals. In human studies,in addition to prevention of T2DM, metformin alsoprevents cardiovascular diseases131 and is associatedwith less cancer132 in T2DM. Furthermore, elderlyindividuals over 70 years of age with T2DM treatedwith metformin have significantly less mortalitythan nondiabetic subjects with fewer diseases andless obesity.133 Acarbose not only prevented T2DMbut also achieved a !50% reduction in cardiovascu-lar end points in prediabetic subjects.134 Metforminhas multiple aging-relevant actions at the cellularand organismal levels, including activation of AMP-

activated kinase, decreased insulin levels, decreasedinsulin/insulin-like growth factor-1 (IGF-1) signal-ing, inhibition of mTOR, inhibition of mitochon-drial complex I in the electron transport chain, andreduction of endogenous production of ROS, butwhether it is a superdrug or whether one or moremechanism retards aging is unclear. Similarly, whileacarbose, an #-glucosidase inhibitor, is largely unab-sorbed in the intestine and slows the absorptionof glucose, its antidiabetic mechanism is probablynot the same mechanism responsible for longevitybecause correcting glucose by other treatments isnot associated with similar outcomes. Therefore,understanding drug mechanisms of action providesinsight for both elderly and diabetic patients toincrease translation and intervention for the devel-opment of the next generation of treatments.

Metabolism is also controlled by hypothalamicneuron circuits that affect peripheral metabolism.Insulin, leptin, and nutrients administered next to orinto the hypothalamus can modulate insulin actionin the periphery. Some of those circuits fail in aging;however, administration of IGF-1 seems to restorethem. Indeed, insulin or IGF-1 actions in the brainare extended to other organs and are associated withAD,135 which may have significance for treatment ofmetabolic and cognitive diseases.

Does diabetes accelerate aging of ! cellsthrough hyperglycemia (glucose toxicity)and also insulin resistance?

Jeffrey B. HalterA consistent decline of ! cell function and insulinsecretion is a hallmark of aging, as demonstratedin rodents and humans.99 Aging effects includea decline of both pancreatic islet cell prolifera-tion and ! cell turnover.100,101 The decline in isletproliferative capacity with age in normal mice ismodest. However, this aging effect is much moredramatic when the proliferative response of olderanimals to partial pancreatectomy, streptozotocin,and exendin-4 (a GLP-1 agonist) is compared withthe robust responses observed in young animals.101

Similarly, young mice are able to increase islet massand ! cell proliferation in response to high-fat diet,but older mice cannot.102 Thus, loss of islet pro-liferative capacity appears to occur early in life inrodents. Exposure to high concentrations of glucosein vitro can lead to apoptosis of ! cells, evidence of



Figure 2. Model for age-related hyperglycemia. Reprintedfrom Ref. 104

glucose toxicity.99 Islets from older Sprague Dawleyrats appear to be more sensitive to glucose-inducedapoptosis.100

Pancreatic ! cell proliferation appears to bedependent on cell cycle regulation. There is asubstantial increase in expression of the cell cycleregulator p16 in islet tissue from older mice whodemonstrate the age-related decline in islet prolif-eration. Overexpression of p16 markedly reducesislet proliferation in younger mice to a level similarto that observed in older mice, and knockout ofp16, preventing p16 from increasing with aging,appears to reverse the age-related decline of islet cellproliferation in this model.103 Furthermore, p16is one of the proteins produced from the CDKN2alocus. Genetic variation at this locus has emergedas a consistent association with type 2 diabetes riskfrom genome-wide scanning studies in humans.

Findings from humans parallel age-relatedchanges observed in rodents, including diminishedinsulin secretion in vitro and in vivo, diminishedproliferative capacity, and increased sensitivity tothe apoptotic effects of high glucose exposure.99

A conceptual model for the interaction of agingand diabetes is provided in Figure 2. In the settingof the age-related impairment of ! cell function,there is a maladaptive response to lifestyle-relatedinsulin resistance, leading to more impaired insulinsecretion and progression to impaired glucose tol-erance (prediabetes) and type 2 diabetes. Glucosetoxicity from chronic exposure to hyperglycemia,in turn, can contribute directly to insulin resistanceand to further impairment of pancreatic ! cell func-tion. In this way, hyperglycemia of diabetes maydrive further worsening of ! cell function and pro-liferation associated with aging.

Metabolic microvascular dysfunctionas a driver of organ aging

Rosario Scalia and Satoru EguchiLeukocyte–endothelium interaction is a physiologicprocess necessary to avert development of infectiousdisease. In contrast to its beneficial role within theimmunologic response and defense mechanisms,leukocyte trafficking appears to also be involved inthe pathogenesis of organ tissue damage in chronicmetabolic disorders. Indeed, increased leukocytetrafficking in response to hyperglycemia and insulinresistance has been linked with damage to bloodvessels and surrounding tissue in diabetes, owingto the production of inflammatory mediators byactivated leukocytes.45–47 Physiologically, phago-cytic leukocytes perform most of their functionsin the extravascular compartment. To reach thiscompartment, they must traverse the vascularendothelium. Therefore, interaction of circulatingleukocytes with the vascular endothelium is apreliminary, essential step in the inflammatoryresponse, and this event occurs on the venular sideof the microcirculation.48 Leukocyte–endotheliuminteractions occur in three steps, each mediated bya specific set of cell adhesion molecules expressedon the endothelial cell surface: (1) leukocyterolling (selectin family adhesion molecules (P-selectin, E-selectin)); (2) leukocyte adherence(immunoglobulin family adhesion moleculesICAM-1 and VCAM-1); and (3) leukocyte extrava-sation (ICAM-1 and PECAM-1). Upregulation ofcell adhesion molecules occurs in spontaneouslyhyperglycemic and obese mice.49,50 Circulating lev-els of soluble ICAM-1 and VCAM-1 are increased indiabetic and obese patients.51,52 Elevated ambientglucose causes increased leukocyte rolling andleukocyte adherence in cultured endothelial cellmonolayers.53 It has also been observed thatmonocytes isolated from diabetic patients aremore adhesive to cultured human endotheliumthan those obtained from normal subjects.54–56

Taken together, these data strongly indicate that apathological inflammatory response characterizedby enhanced endothelial adhesiveness and increasedleukocyte–endothelium interactions occurs in themicrovasculature during metabolic disorders. Atthe mechanistic level, loss of physiologic endothelialnitric oxide (eNO) appears to be correlated with the



vascular inflammation of metabolic disorders.57,58

We and others have demonstrated that loss of basaleNO levels in postcapillary venules rapidly inducesinflammatory responses in the microcirculation,characterized by increased leukocyte–endotheliuminteractions and upregulation of endothelial celladhesion molecules.59,60

This inflammatory microangiopathy is likely tobe a key contributing factor to accelerated aging.Indeed, the aging vascular endothelium experiencesa progressive loss of release of eNO, associated withendothelial dysfunction.61 Reduced release of NOin response to endothelium-dependent agonists hasbeen demonstrated in aged arteries, including thebrachial artery62 and coronary artery63 in humansand the aorta,64 carotid artery,65 and mesentericartery66 in rats. The mechanism responsible for thisage-related endothelial dysfunction has not yet beenclearly elucidated, but it might involve (1) changesin expression/and or coupling of eNOS,67–69 (2)increased breakdown of eNO due to an augmentedproduction of reactive oxygen species (ROS),70,71 or(3) a gradual loss of antioxidant capacity that nor-mally provides cellular protection against ROS.72,73

The loss of physiologic eNO with aging appears toalso be correlated with vascular inflammation. Thus,aging is associated with enhanced expression ofadhesion molecules in the rat aorta74 and increasedadhesion of monocytes to the endothelial cell surfacein the rabbit aorta.75 Remarkably, serum-solublelevels of ICAM-1 and other adhesion molecules arealso elevated with aging in humans.76 Endothelialdysfunction and inflammatory phenotypes in theaging vasculature have been linked to damage oflarge conduit vessels. Studies in aging laboratoryanimals have demonstrated that reduced eNOS lev-els, associated with vascular inflammation, causeapoptosis of coronary endothelial cells77,78 andaccumulation of atherogenic glycosaminoglycans atthe arterial wall.75 We have reported the occur-rence of increased leukocyte–endothelium interac-tions in the aging F1-F344xBN rat.79 The impor-tance of this research is underscored by the factthat, in humans, the incidence of coronary arterydisease,80,81 hypertension,82 and congestive heartfailure83,84 greatly increases with aging, indepen-dent of other risk factors. Thus, a full under-standing of the cellular mechanisms by whichmetabolic disorders cause alteration in microvas-cular function is likely to shed new light on

the relationship between metabolic disorders andaging.

How does diabetes affect the seven pillarsof aging in the kidney?

Balakuntalam S. KasinathOlder age is a risk factor for end-stage kidney dis-ease, the most common cause of which is diabetes.Conversely, diabetes induces senescence in the kid-ney independent of age.85 Thus, there is a mutuallyreinforcing interaction between diabetes and agingin kidney injury that merits further investigation.Diabetes causes glomerulosclerosis, tubulointersti-tial fibrosis, and vascular disease, leading to progres-sive loss of kidney waste-clearance function. Agingis also associated with similar histologic lesions inthe kidney (nephrosclerosis); in addition, ischemicchanges and glomerular collapse may be seen. Here,I review the scant information that is available on theinteraction between diabetes and aging in the con-text of the pillars of aging. In most of the categoriesbelow, diabetes and aging have been separately stud-ied; however, their interplay has not been exploredin depth.

Diabetes is associated with increased oxidativestress in the kidney that is augmented by aging.86

Aging appears to stimulate mitochondrial gener-ation of ROS in the kidney,87 whereas this maynot be the case in diabetes.88 Clinical observationsshow that, in the presence of preexisting kidneydisease, diabetes and aging are risk factors forischemic stress-induced injury to the kidney. Howaging and diabetes interact in the kidney’s responseto the aforementioned stress factors remains to beexplored.

In both diabetes and aging, monocyte infiltrationis commonly seen in the kidney. Kidney cell nuclearlocalization of NF-$B, a master regulator of cytokineexpression, is increased in aging rodents.89 Exuber-ant inflammatory response appears to contribute tothe demise of type 2 diabetic mice. The life span ofdb/db mice with type 2 diabetes is about 1 year, sig-nificantly less than that of nondiabetic mice; whiletumors are the main cause of death in nondiabeticmice, we observed that suppurative inflammation isthe main cause of fatality in db/db diabetic mice.90

Thus, diabetes shortens the life span and changesthe cause of death in mice. Diabetes also appears tochange the type of tumors that occur in aging db/dbmice.90 More work is needed to explore the kidney’s



adaptation to inflammation and infection in agingdiabetic mice.

Both aging and diabetes are associated withendoplasmic reticulum stress in the kidney.Impaired autophagy contributes to kidney injury indiabetes.91 Impaired renal autophagy also occurs inaging, probably due to Sirt1 deficiency.92 Whetheraging and diabetes together augment autophagyimpairment accelerating kidney injury requiresinvestigation. Although ER stress inhibits generalprotein synthesis, synthesis of specific proteins,including matrix proteins, appears not to be inhib-ited, contributing to kidney fibrosis in both ofthese conditions. A new related development is thatendogenous hydrogen sulfide regulates protein syn-thesis in the kidney. Hydrogen sulfide content inthe kidney is reduced in diabetes; sodium hydro-sulfide, a source of hydrogen sulfide, ameliorateskidney injury in diabetic rodents.93 Hydrogen sul-fide inhibits high glucose-induced protein synthesisin renal cells in vitro by stimulating AMP-activatedprotein kinase, which leads to inhibition of mTOR.94

We have observed that the kidney hydrogen sulfidecontent is reduced in aging mice (unpublished data).Whether administration of hydrogen sulfide ame-liorates aging-induced kidney injury is unknown.Whereas rapamycin, an inhibitor of mTOR, pro-longs life span in nondiabetic mice, it augmentsmortality in db/db diabetic mice;90 the mechanis-tic basis of this differential response requires futureexploration. Hydrogen sulfide has been reported tomediate dietary restriction–induced protection ofthe kidney against ischemic injury and extension oflife span in worms and yeast.95

Infusion of early endothelial outgrowth cellsseems to improve senescence, induce autophagy,and ameliorate kidney injury in diabetic mice.96

Infusion of bone marrow cells from young miceameliorates senescent changes in the kidney in oldmice.97 Whether stem cells aid in ameliorating kid-ney damage in aging diabetic mice needs to beinvestigated.

DNA damage occurs in the kidney in diabetes andaging. Recent reports indicate that epigenetic acety-lation markers are increased within genes related toinflammation in peripheral blood monocytes fromdiabetic patients with renal and retinal damage.98

Epigenetic mechanisms in the aging kidney are notwell understood.

In summary, the interaction of diabetes and agingin the kidney may occur by the potentiation of thesame mechanistic pathways or by recruitment ofdifferent pathways that lead to the same pheno-type. With rising life span and increasing preva-lence of diabetes, it is very likely that we will haveto contend with increasing numbers of older adultswith diabetic kidney disease. Meaningful interven-tion to reduce morbidity and mortality in thispopulation requires better understanding of theunderlying mechanisms.

Understanding and mitigating prematureaging due to cancer and chemotherapy

Arti HurriaThe hallmarks of aging can be utilized as a frame-work with which to understand the impact ofcancer therapies on the aging trajectory. The pri-mary mechanisms of action of several cancer treat-ments affect specific hallmarks of aging, such asgenomic instability, cellular senescence, and stemcell exhaustion.6 Furthermore, the primary impactof cancer itself on the patient can accelerate theaging process. Hence, cancer and cancer therapyplace patients at risk of a premature aging syndrome,thus serving as a potential human model for under-standing the aging process.

Receipt of chemotherapy is a physiologic stressor,which unmasks an individual’s physiologic reserve.Some patients are able to tolerate treatment with-out undue side effects, whereas others experiencemajor side effects that limit the ability to delivertreatment. Cancer and cancer treatment can cre-ate symptoms consistent with the frailty phenotypedescribed by Fried and colleagues, including slow-ness, weakness, weight loss, low activity, and fatigue.When a patient completes the chemotherapy course(if no further treatment is required), the patient willrecover; however, this rate of recovery is variable.Hence, the receipt of treatment can be considered ahuman model of accelerated aging brought on by aphysiologic stressor, and, when the stressor is with-drawn, there is opportunity to study the individuals’resilience (i.e., their ability to bounce back to theirprior level of functioning).

Although patients recover upon completionof chemotherapy, there is concern in the can-cer literature that we have placed patients onan accelerated aging trajectory. This hypothesis



is supported by data collected from cancer sur-vivors who report poorer physical function,120,136,137

poorer quality of life,138,139 and increased num-ber of comorbidities,140,141 as well as riskfor cognitive decline.142,143 The underlying can-cer treatment may affect telomere length,144–147

increase p16 expression,123 increase proinflamma-tory cytokines,148,149 and increase resting energyexpenditure.150,151

There are several unanswered questions. Howdoes cancer treatment affect the aging trajectory?Are patients who receive cancer treatment on adifferent trajectory of aging that parallels normalaging (the phase-shift hypothesis) or are they nowon an accelerated aging trajectory where functionaldecline is accelerated in comparison to normalaging (the accelerated-aging hypothesis). Are thesechanges reversible and, if so, what interventions areneeded in order to reset to a normal aging trajectory?How does aging affect cancer biology and progres-sion? How can cancer and cancer therapy be usedto further our understanding of the molecular pil-lars of aging? All of these questions are importantresearch directions that can not only inform the risksand benefits of cancer therapy but also be utilized asa model to understand human aging and resilience.

How does activation of inflammatory andcoagulation pathways in cancer patientsaffect survivorship and functional status?

Harvey Jay CohenThere is a strong epidemiologic association betweenmarkers of inflammation and activation of the coag-ulation system with functional decline and survivalin non-cancer-bearing older adults, which are pre-dictive of subsequent decline.105 Moreover, canceralso induces activation of these two systems, andinflammation has been included as one of the hall-marks of both cancer and aging.6,106 Thus, a poten-tially vicious cycle exists in a patient with cancersuch that aging might affect the progress of cancerdevelopment and that cancer might affect the pro-cess of aging simultaneously. Moreover, the intro-duction of cancer treatments might also acceleratethe latter process. Figure 3 indicates possible path-ways involved and how they might affect survivaland function.

Thus, inflammation may be initiated in cancerpatients by the increased numbers of neutrophilsand their activation, which can produce increased

adhesion and release of free radicals; simulta-neously, predominantly via the NF-$B pathway,there is increased IL-6, VCAM, IL-1!, and TNF-#produced. Concomitantly, coagulation is activatedby tissue factor (TF) release, and the procoagu-lant state produces D-dimers and fibrin crosslink-ing. Endothelial activation occurs, indicated byincreased VCAM, adhesion, and ROS. There is directinterplay between these two systems, as D-dimerscan increase synthesis and release of IL-1! andPAI-1 from macrophages in vitro and TF caninduce production of NF-$B, IL-6, and VCAM.107

Thus, this is essentially one interconnectedsystem. Treatment can likewise activate these path-ways, in part via free radical generation, espe-cially for chemotherapy and radiation therapy. Theimpact of immunotherapy is not clear, althoughcheckpoint inhibitors release immune system inhi-bition with toxic effects on the host acutely, butthe long-term impact is unknown. Treatment candirectly affect organ function as well (e.g., anthra-cycline effect on the heart). Cancer can also resultin an increase in p16 and decreased telomerelength, which may lead to an increase in senes-cent cells and further release of inflammatoryfactors, as discussed by Campisi.

The impact of these pathway activations resultsin organ and vascular damage. For example, IL-6and other inflammatory factors induce the cachexiasyndrome; in animal models, fatigue, weakness,and cognitive decline are produced by injectionof inflammatory cytokines; IL-6 produces mus-cle wasting and bone loss in experimental ani-mals; atherosclerosis, another pathway to fatigueand weakness, is induced; GFR is reduced, andinflammation suppresses bone marrow function,resulting in anemia. The cumulative effect of suchorgan damage can produce a chronic multiple organdysfunction syndrome (CMODS), a chronic anal-ogy of what is frequently seen in intensive careunits in conditions like sepsis, which similarly butacutely activate the inflammatory and coagulationsystems.108 The CMODS might then produce apremature aging or frailty phenotype resulting indecreased function and shorter survival.109

Questions still to be answered include (1)whether we can establish further direct exper-imental evidence that cancer-related inflam-mation/coagulation activation produces organdamage, (2) whether there are common mediators



Figure 3. Inflammation/coagulation in cancer and aging.

across organ systems or unique ones for each,and (3) whether these pathways are targetable toimprove function and survivorship as people age.

Which animal and/or cellular modelsare best for studying the effects of cancerand cancer therapy on the aging process?

Judith CampisiA relatively underappreciated effect of manymalignant tumors is their ability to cause genomicdamage or damage responses in distal tissues.110

More generally, paraneoplastic syndromes—symptoms that are due to cancer but not to thelocal presence of cancer cells—have been knownfor decades.111 In both cases, the ability of tumorsto affect distal tissues is thought to derive fromcirculating tumor-derived cytokines, hormones,and other factors. Notably, the indirect effectsof cancers—which include neurological deficits,thrombocytosis, anemia, glomerulonephritis, andother symptoms—partially overlap with pheno-types and pathologies that are common amongnondiseased elderly. Thus, cancer, a major age-related disease itself, can also drive the developmentof noncancer pathologies associated with aging.

Related to drivers of aging phenotypes andpathologies are many of the cytotoxic and genotoxictherapies that are commonly used to treat cancer.Recent studies show that children who were suc-cessfully treated for leukemia or lymphoma and arenow middle-aged adults suffer from a host of age-related diseases that are characteristic of much olderindividuals.112

Many anticancer therapies are potent induc-ers of cellular senescence, a tumor-suppressivestress response that entails an irreversible arrest ofcell proliferation and development of a complexsenescence-associated secretory phenotype (SASP)that includes a host of inflammatory cytokines,chemokines, growth factors, and proteases.113

Senescent cells accumulate with age in many mam-malian tissues, and many anticancer therapies resultin a long-term burden of senescent cells. The per-sistent presence of senescent cells, and especially theproinflammatory SASP, is thought to be significantdriver of numerous age-related diseases.114

Recently, transgenic mouse models have beendeveloped in which it is possible to selectivelyeliminate senescent cells. These models show thatsenescent cells are responsible for a number ofadverse phenotypes caused by anticancer therapies.These adverse phenotypes include the developmentof cancer metastases, cardiotoxicity (which oftenlimits the use of these therapies), loss of hemosta-sis, and loss of robust physical activity—phenotypesand pathologies that also increase during aging.

Many questions remain unanswered regardinghow cancer and its treatments can drive aging.For example, both tumors and the senescent cellsinduced by cytotoxic/genotoxic therapies secretemany molecules that are proinflammatory immuneactivators. Very little is known about which ofthese secreted factors are most important foractivating the immune system, which immunecomponents are most important for the proagingresponses, and whether the secreted factors can



drive aging phenotypes independent of the immunesystem. Likewise, little is known about which distaltissues are most affected by tumors, which tissuesaccumulate the most senescent cells after anticancertherapies, and which tissues are most important forthe resulting aging phenotypes and pathologies.

What types of interventions might be developedto alleviate the effects of tumors and anticancertherapies on age-related phenotypes and patholo-gies? Once specific SASP factors are identified assignificant drivers, is should be possible to developtherapies to neutralize them or their targets. How-ever, given the complexity of the secretomes oftumors and the SASP,113 the proaging effects mightbe caused by multiple factors, thus diminishing theefficacy of single-agent interventions. As the regu-latory pathways that activate and maintain tumorsecretomes and the SASP are identified, strategiescan be developed to prevent the development ofthis phenotype by specifically targeting these path-ways. For example, much of the SASP is controlledby p38MAPK and NF-$B,115 for which inhibitorydrugs have already been developed. A disadvan-tage of this approach is that it requires the con-tinuous presence of the inhibitory drugs, increasingthe risk of adverse side effects. A third strategy is todevelop drugs that can selectively eliminate senes-cent cells, similar to the effects of the transgene inthe mouse models. At least one such drug (ABT-263)was recently identified,116 although additional effortwill be need to optimize this drug and/or developalternatives.

Functional decline in the older cancerpatient: can lifestyle interventions turnback the hands of time? And if so, throughwhat mechanism?

Wendy Demark-WahnefriedThe number of cancer survivors in this country isexpanding rapidly, given converging trends towardaging and improvements in early detection andtreatment. In 2014, there were roughly 14.5 millionsurvivors in the United States, and projections indi-cate that this number will approach 19 million by2024.117 This patient population provides an opti-mal model to study aging, not only because of risingnumbers of survivors and the fact that most (61%)are age 65 years and older,117 but also more impor-tantly because decades of research evidence shows

Figure 4. Kilogram change in fat (dashed line) and lean (solidline) body mass among 36 breast cancer patients receiving adju-vant chemotherapy. Adapted from Ref. 118

that the process of aging appears to speed up oncethe cancer diagnosis is rendered.

An example of accelerated aging is providedby longitudinal research on body compositionthat measures change in lean and fat mass afterdiagnosis (Fig. 4).118 Studies initiated in the1990s among breast cancer patients receivingadjuvant chemotherapy show significant increasesin adiposity and concurrent losses in muscle inthe year following diagnosis. The changes in bodycomposition that these patients undergo in 1 yearare comparable to 10 years of normal aging. Theseresults have been replicated time and again amongbreast cancer patients, as well as those with otherforms of cancer.119 The increase in fat mass mostlikely contributes to a hyperinflammatory stateamong these survivors, and the decrease in musclemass may be an underlying cause of the accelerateddecline in physical functioning experienced by thesecancer survivors—declines that affect the abilityto work, perform activities of daily living, and liveindependently.120 Moreover, it is hypothesized thatthe decreases in body protein detected by fairlyimprecise methods, such as dual X-ray absorp-tiometry, are also likely to manifest in changes inlevels of circulating binding proteins, hormones,and other key constituents that are involved inaging, such as DNA repair, immune response,and mitochondrial integrity. Cancer and its manyforms of treatment are also likely to influence themicrobiome, as well as to induce a broad landscapeof epigenetic changes that regulate aging.

While previous studies show that some indi-viduals are either resistant and do not succumbto these common cancer- or treatment-inducedadverse effects or are resilient and able to bounce



back from such adversity, the predictors that por-tend future health span are currently unknown.Therefore, an opportunity to gain insights into themechanisms of aging exists through the longitudinalstudy of these populations.

Another research opportunity that may informaging research lies in studying the response of can-cer survivors to interventions. A healthy lifestylemay be important in restoring body compositionand functioning to baseline levels. A handful ofstudies promoting physical activity and a health-ful diet and body weight have been conducted todetermine if the trajectory of functional declineamong cancer survivors can be hindered or reversed.To date, the largest study was the Reach-out toENhancE Wellness (RENEW) in Older Cancer Sur-vivors trial, a two-arm randomized controlled trialamong 641 older (age 65+) overweight or obese sur-vivors of breast, prostate, or colorectal cancer in theUnited States, Canada, and the United Kingdom.121

The intervention, which promoted a slow rate ofweight loss, a plant-based diet, and resistance andendurance exercise via telephone counseling, andtailored, mailed print materials, effectively sloweddeclines in physical functioning compared withwaitlisted controls. Secondary analyses showed thatsurvivors who were most likely to benefit from theintervention were those with fewer comorbiditieswho either were not as obese at baseline or lostgreater amounts of weight over the study period.Other lifestyle interventions in this patient popu-lation also show improvements in physical func-tion or performance with concomitant reductions inbiomarkers associated with inflammation (e.g., IL-6, IL-8, C-reactive protein) and energy metabolism(e.g., insulin, c-peptide), with preliminary datagathering on telomerase. Therefore, studying theresponse to lifestyle interventions, as well as inter-ventions that may be more intensive in this patientpopulation, may also provide insights not only intothe molecular and cellular mechanisms that causeaccelerated aging but also to solutions that maypotentially turn back the hands of time.

How does cancer treatment affectcognitive aging?

Tim A. AhlesCancer treatments, including chemotherapy andradiation, endocrine, and immune therapies, cancause long-term alterations in cognitive function

among a subgroup of vulnerable patients. Risk fac-tors for posttreatment decline are similar to fac-tors that influence normal cognitive aging, includingage, cognitive reserve, genetic factors (apolipopro-tein E, catechol-O-methyltransferase, and brain-derived neurotrophic factor), comorbid conditions,and frailty.122 Cancer treatments can have effectson specific brain structure and function. How-ever, cancer treatments also affect multiple sys-tems associated with the biology of aging, includingcausing (1) DNA damage, (2) chronic inflamma-tion, (3) cell senescence, (4) oxidative stress, (5)depletion of stem cell reserve, and (6) shorteningof telomeres.122 Recent research has demonstratedactivation of pathways associated with aging, suchas increased expression of p16INKa and ARF inbreast cancer patients treated with chemotherapy123

and activation of ERK and AKT signaling pathwaysin a rat model of chemotherapy-induced cognitivechange.124 Further, cancer treatment affects brainstructure and function associated with the agingbrain, including volume reduction and decreases inactivation, white matter integrity, vascularization,and neurotransmitter activity.122

Taken together, the above findings suggest thatcancer treatments interact with and may accel-erate cognitive aging through affecting a broadarray of biological systems associated with aging.Accommodation of specific and systemic effects ofcancer treatment on cognitive aging requires uti-lization of broad-based systems theories of aging.Network/engineering/redundancy theories of agingposit that complex biological systems have evolvedhighly redundant systems that create resiliencythrough tolerance to local system failure.125 How-ever, redundancy also leads to damage accumu-lation, particularly if repair mechanisms are notoptimal. Since the brain has limited capacity forrepair, damage accumulation is particularly prob-lematic. Therefore, multiple patterns of failure canlead to increased vulnerability to cognitive agingthrough effecting specific systems and/or increasingrandom error/failure. Sophisticated mathematicalmodels based on graph theory are being developedthat simulate activity within complex biological sys-tems, including the brain.125 An advantage of thesemodels is that patterns of failure rate can be simu-lated to examine the impact on the system, therebygenerating hypotheses that can be tested in humanand animal studies. Consequently, mathematical



models of complex systems may be an impor-tant future addition to translational research effortsexamining the interface of cognitive aging and can-cer treatments.

The network biology approach described abovesuggests the need to evaluate resiliency across mul-tiple biological systems. Allostatic load refers tocumulative physiological dysregulation related to alifetime of adapting to exposure to physiological andpsychological demands.126 Accumulation of allo-static load occurs when adaptive responses to chal-lenges chronically fall outside the normal operatingrange, resulting in wear and tear on the multiplecomponents of the regulatory system. Consistentwith network theories, these physiological and psy-chological challenges can increase failure accumula-tion across biological systems, resulting in decreasedresiliency. Measurement of allostatic load is opera-tionalized as the assessment of biological parametersrelated to risk of disease across several biological sys-tems, including the HPA axis, sympathetic nervoussystem, immune system, cardiovascular system, andmetabolic processes. To date, numerous studies havedemonstrated that high levels of allostatic load areassociated with risk of mortality, development ofspecific diseases and frailty, and cognitive declineassociated with aging. Allostatic load captures thecombined effect of multiple biological systems thathave individually been found to predict age-relatedcognitive decline.126

Unanswered questions for future research include(1) which models that describe the resiliency andfailure of complex systems are most appropriate forguiding research related to interactions of aging pro-cesses, cancer, and cancer treatments in determiningcognitive aging? (2) what panel of biomarkers acrossbiological systems best captures system resiliencyand vulnerability? and (3) which advanced statis-tical models hold potential for understanding howbrain structure and function change with aging andin response to insults to the brain caused by cancerand cancer treatments?

Conclusions and recommendations

The Second Geroscience Summit, exploring diseasedrivers of aging, brought together a broad range ofscientists to discuss issues relevant to basic biology ofaging, translation, and clinical practice. In additionto the scientific presentations, briefly described in

the text, many additional participants contributedvigorously to the discussions.

Perhaps the most relevant conclusion from thediscussions is that geroscience is probably thebest platform to address the complex interactionsbetween aging and chronic diseases, not solely asstated in the original concept (aging is the majorrisk factor for diseases), but also as a two-way street,where diseases also accelerate the pace of aging.Equally important is the growing realization thathealth is more than the absence of disease, and, thus,when an individual is affected by a major disease, thework of the health provider is not done, since evenif the disease is eradicated, full health is often not yetfully restored. In this context, the possibility of using“anti-aging” approaches as coadjuvants in diseasefighting emerges as an exciting and promising alter-native. Of course, much work remains to be done inorder to arrive at that end, including the identifica-tion of biomarkers for the different pillars of agingand further characterization of the individual pil-lars most directly affected by the disease and/or thetreatment. In that context, it is useful to rememberthat, while the pillars of aging are often discussed asindependent entities, it is well accepted that changesin any of them often affect the other pillars. In thatmanner, it is possible to conclude that a given dis-ease/treatment pair affects all the pillars of aging,which complicates future studies and decisions con-cerning possible therapeutic approaches. Thus, it iscrucial to carefully dissect which pillars of aging areaffected directly, earlier, and/or the most. In addi-tion, every individual is likely to be affected in adifferent manner, and thus individualized medicinewill be necessary.

As discussed at the summit, it has become clearthat the physiological impact of diseases or theirtreatments can indeed accelerate the phenotypesof normal aging. Among those phenotypes, it isimportant to consider an increased susceptibility toadditional major chronic diseases. Another area ofresearch uncovered during the discussions pertainsto the need to consider early exposure to disease asa possible confounder in studies focused on inter-ventions that may reduce the rate of aging, againpointing to the need to consider individual differ-ences in likely susceptibilities and needs.

Finally, the close relationship between the basicbiology of aging and the basic biology of dis-ease indicates the importance of fostering further



interdisciplinary research, where scientists inter-ested in different diseases might collaborate withresearchers interested in aging to the enhanced ben-efit to both partners.

Conflicts of interest

The authors declare no conflicts of interest

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Disease drivers of aging - Demystifying Medicine › dm17 › m01d... · Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue:Annals Reports Disease