Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-cd9895bd7-8ctnn Total loading time: 0 Render date: 2024-12-26T09:04:46.824Z Has data issue: false hasContentIssue false

Chapter 2 - Biology of Aging

from Section I - General Approach to the Care of the Elderly

Published online by Cambridge University Press:  30 June 2022

By
Allyson K. Palmer  and
James L. Kirkland
Edited by
Jan Busby-Whitehead ,
Samuel C. Durso ,
Christine Arenson ,
Rebecca Elon ,
Mary H. Palmer  and
William Reichel
Jan Busby-Whitehead
Affiliation:
University of North Carolina, Chapel Hill
Samuel C. Durso
Affiliation:
The Johns Hopkins University, Maryland
Christine Arenson
Affiliation:
Thomas Jefferson University, Philadelphia
Rebecca Elon
Affiliation:
The Johns Hopkins University School of Medicine
Mary H. Palmer
Affiliation:
University of North Carolina, Chapel Hill
William Reichel
Affiliation:
Georgetown University Medical Center
Get access

Summary

Exciting advances have been made recently in understanding the mechanistic underpinnings of aging. Mounting evidence suggests that progression of aging changes can be modulated. Interventions that extend health span and lifespan in model organisms have been developed. The time is approaching for translation of these interventions into clinical treatments. By targeting fundamental aging mechanisms, it may be possible to delay, prevent, or alleviate chronic diseases as a group, rather than individually, and enhance health span. Such a compression of morbidity would have profound clinical and economic benefits, with reductions in life-years spent with chronic disease and age-related dysfunction. However, barriers remain, including lack of clinical and regulatory paradigms for translating agents that target fundamental aging processes into clinical interventions, and a shortage of personnel trained to do so. Here we consider research findings that support the potential value of translational aging research and strategies to move these findings from bench to bedside.

Keywords

gerosciencehealth spansenolyticsagingclinical trialslongevity dividend
Type
Chapter
Information
Reichel's Care of the Elderly
Clinical Aspects of Aging
 , pp. 12 - 20
Publisher: Cambridge University Press
Print publication year: 2022

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Goldman, DP, Cutler, D, Rowe, JW, Michaud, PC, Sullivan, J, Peneva, D, Olshansky, SJ. Substantial health and economic returns from delayed aging may warrant a new focus for medical research. Health Affairs. 2013; 32(10):1698–1705.Google Scholar
Hung, WW, Ross, JS, Boockvar, KS, Siu, AL. Recent trends in chronic disease, impairment and disability among older adults in the United States. BMC Geriatr. 2011; 11:47.Google Scholar
Fontana, L, Partridge, L, Longo, VD. Extending healthy life span: From yeast to humans. Science. 2010; 328(5976):321–326.Google Scholar
Kirkland, JL. Translating the science of aging into therapeutic interventions. Cold Spring Harb PerspectMed. 2016; 6(3):a025908.CrossRefGoogle ScholarPubMed
Lopez-Otin, C, Blasco, MA, Partridge, L, Serrano, M, Kroemer, G. The hallmarks of aging. Cell. 2013; 153(6):1194–1217.Google Scholar
Tchkonia, T, Kirkland, JL. Aging, cell senescence, and chronic disease: Emerging therapeutic strategies. JAMA. 2018; 320(13):1319–1320.CrossRefGoogle ScholarPubMed
Kirkland, JL, Tchkonia, T. Cellular senescence: A translational perspective. EBioMedicine. 2017; 21:21-28.Google Scholar
Longo, VD, Antebi, A, Bartke, A, Barzilai, N, Brown-Borg, HM, Caruso, C, et al. Interventions to slow aging in humans: Are we ready? Aging Cell. 2015; 14(4):497–510.Google Scholar
Christensen, K, Doblhammer, G, Rau, R, Vaupel, JW. Aging populations: The challenges ahead. Lancet. 2009; 374(9696):1196–1208.Google Scholar
St Sauver, JL, Boyd, CM, Grossardt, BR, Bobo, WV, Finney Rutten, LJ, Roger, VL, et al. Risk of developing multimorbidity across all ages in an historical cohort study: Differences by sex and ethnicity. BMJ Open. 2015; 5(2):e006413.CrossRefGoogle Scholar
Kennedy, BK, Berger, SL, Brunet, A, Campisi, J, Cuervo, AM, Epel, ES, et al. Geroscience: Linking aging to chronic disease. Cell. 2014; 159(4):709–713.CrossRefGoogle ScholarPubMed
Fried, LP, Xue, Q-L, Cappola, AR, Ferrucci, L, Chaves, P, Varadhan, R, et al. Nonlinear multisystem physiological dysregulation associated with frailty in older women: Implications for etiology and treatment. J Gerontol A Biol Sci Med Sci. 2009; 64(10):1049–1057.Google Scholar
Olshansky, SJ, Carnes, BA, Cassel, C. In search of Methuselah: Estimating the upper limits to human longevity. Science. 1990; 250(4981):634–640.Google Scholar
Rockwood, K, Mitnitski, A, Song, X, Steen, B, Skoog, I. Long-term risks of death and institutionalization of elderly people in relation to deficit accumulation at age 70. J Am Geriatr Soc. 2006; 54(6):975–979.Google Scholar
Andersen, SL, Sebastiani, P, Dworkis, DA, Feldman, L, Perls, TT. Health span approximates life span among many supercentenarians: Compression of morbidity at the approximate limit of life span. J Gerontol A Biol Sci Med Sci. 2012; 67(4):395–405.CrossRefGoogle ScholarPubMed
Ikeno, Y, Hubbard, GB, Lee, S, Dube, SM, Flores, LC, Roman, MG, Bartke, A. Do Ames dwarf and calorie-restricted mice share common effects on age-related pathology? Pathobiol Aging Age Relat Dis. 2013; 3.Google Scholar
Miller, RA. “Dividends” from research on aging: Can biogerontologists, at long last, find something useful to do? J Gerontol A Biol Sci Med Sci. 2009; 64(2):157–160.CrossRefGoogle ScholarPubMed
Olshansky, SJ, Perry, D, Miller, RA, Butler, RN. Pursuing the longevity dividend: Scientific goals for an aging world. Ann N Y Acad Sci. 2007; 1114:11–13.CrossRefGoogle ScholarPubMed
Hurria, A, Carpenter, CR, McFarland, F, Lundebjerg, NE, de Cabo, R, Ferrucci, L. Models and studies of aging: Executive summary of a report from the U13 Conference Series. J Am Ger Soc. 2019; 67(3):428–433.CrossRefGoogle ScholarPubMed
Liang, H, Masoro, EJ, Nelson, JF, Strong, R, McMahan, CA, Richardson, A. Genetic mouse models of extended lifespan. Exp Gerontol. 2003; 38(11–12):1353–1364.Google Scholar
Kirkland, JL. Translating advances from the basic biology of aging into clinical application. Exp Gerontol. 2013; 48(1):1–5.Google Scholar
Fontana, L, Partridge, L. Promoting health and longevity through diet: From model organisms to humans. Cell. 2015; 161(1):106–118.Google Scholar
Mattison, JA, Roth, GS, Beasley, TM, Tilmont, TM, Handy, AM, Herbert, RL, et al. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature. 2012; 489(7415):318–321.Google Scholar
Colman, RJ, Anderson, RM, Johnson, SC, Kastman, EK, Kosmatka, KJ, Beasley, TM, et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science. 2009; 325(5937):201–204.Google Scholar
Anson, RM, Guo, Z, de Cabo, R, Iyun, T, Rios, M, Hagepanos, A, et al. Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake. Proc Natl Acad Sci USA. 2003; 100(10):6216–6220.CrossRefGoogle ScholarPubMed
Miller, RA, Buechner, G, Chang, Y, Harper, JM, Sigler, R, Smith-Wheelock, M. Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell. 2005; 4(3):119–125.Google Scholar
Solon-Biet, SM, McMahon, AC, Ballard, WO, Ruohonen, K, Wu, LE, Cogger, VC, et al. The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice. Cell Metab. 2014; 19(3):418–430.Google Scholar
Newman, JC, Covarrubias, AJ, Zhao, M, Yu, X, Gut, P, Ng, C-P, et al. Ketogenic diet reduces midlife mortality and improves memory in aging mice. Cell Metab. 2017; 26(3):547–557 e8.CrossRefGoogle ScholarPubMed
Brandhorst, S, Longo, VD. Protein quantity and source, fasting-mimicking diets, and longevity. Adv Nutr. 2019; 10(Suppl. 4):S340–S350.CrossRefGoogle ScholarPubMed
Lee, C, Raffaghello, L, Brandhorst, S, Safdie, FM, Bianchi, G, Martin-Montalvo, A, et al. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci Transl Med. 2012; 4(124):124ra27.Google Scholar
Van Nieuwenhove, Y, et al. Preoperative very low-calorie diet and operative outcome after laparoscopic gastric bypass: A randomized multicenter study. Arch Surg, 2011; 146(11):1300–1305.CrossRefGoogle ScholarPubMed
Campisi, J. Senescent cells, tumor suppression, and organismal aging: Good citizens, bad neighbors. Cell. 2005; 120(4):513–522.Google Scholar
Roos, CM, Zhang, B, Palmer, AK, Ogrodnik, MB, Pirtskhalava, T, Thalji, NM, et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell. 2016; 15(5):973–977.Google Scholar
Xu, M, Palmer, AK, Ding, H, Weivoda, MM, Pirtskhalava, T, White, TA. Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife. 2015; 4:e12997.Google Scholar
Xu, M, Pirtskhalava, T, Farr, JN, Weigand, BM, Palmer, AK, Weivoda, MM, et al. Senolytics improve physical function and increase lifespan in old age. Nature Medicine. 2018; 24(8):1246–1256.Google Scholar
Zhu, Y, Tchkonia, T, Pirtskhalava, T, Gower, AC, Ding, H, Giorgadze, N, et al. The Achilles’ heel of senescent cells: From transcriptome to senolytic drugs. Aging Cell. 2015; 14(4):644–658.Google Scholar
Palmer, AK., Xu, M, Zhu, Y, Pirtskhalava, T, Weivoda, MM, Hachfeld, CM, et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell. 2019:e12950.Google Scholar
Ogrodnik, M, Zhu, Y, Langhi, LGP, Tchkonia, T, Kruger, P, Fielder, E. Obesity-induced cellular senescence drives anxiety and impairs neurogenesis. Cell Metabolism. 2019; 29(5):1061–1077.Google Scholar
Lewis-McDougall, FC, Ruchaya, PJ, Domenjo-Vila, E, Teoh, TS, Prata, L, Cottle, BJ, et al. Aged-senescent cells contribute to impaired heart regeneration. Aging Cell. 2019; 18(3):e12931.Google Scholar
Kim, SR, Jiang, K, Ogrodnik, M, Chen, X, Zhu, X-Y, Lohmeier, H, et al. Increased renal cellular senescence in murine high-fat diet: Effect of the senolytic drug quercetin. Transl Res. 2019; 213:112–123.CrossRefGoogle ScholarPubMed
Musi, N, Valentine, JM, Sickora, KR, Baeuerle, E, Thompson, CS, Shen, Q, et al. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell. 2018; 17(6):e12840.Google Scholar
Zhang, P, Kishimoto, Y, Grammatikakis, I, Gottimukkala, K, Cutler, RG, Zhang, S, et al. Senolytic therapy alleviates Abeta-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nature Neuroscience. 2019; 22(5):719–728.Google Scholar
Farr, JN, Xu, M, Weivoda, MM, Monroe, DG, Fraser, DG, Onken, JL, et al. Targeting cellular senescence prevents age-related bone loss in mice. Nature Medicine. 2017; 23(9):1072–1079.Google Scholar
Justice, JN, Nambiar, AM, Tchkonia, T, LeBrasseur, NK, Pascual, R, Hashmi, NK, et al. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine. 2019; 40:554–563.CrossRefGoogle ScholarPubMed
Hickson, LJ, Prata, LGPL, Bobart, SA, Evans, TK, Giorgadze, N, Hashmi, SK, et al. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019; 47:446–456.Google Scholar
Martin-Montalvo, A, Mercken, EM, Mitchell, SJ, Palacios, HH, Mote, PL, Scheibye-Knudsen, M, et al. Metformin improves healthspan and lifespan in mice. Nature Communications. 2013; 4:2192.Google Scholar
Libby, G, Donnelly, LA, Donnan, PT, Alessi, DR, Morris, AD, Evans, JMM, et al. New users of metformin are at low risk of incident cancer: A cohort study among people with type 2 diabetes. Diabetes Care. 2009; 32(9):1620–1625.Google Scholar
Bannister, CA, Holden, SE, Jenkins-Jones, S, Morgan, CLI, Halcox, JP, Schernthaner, G, et al. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes, Obesity Metabolism. 2014; 16(11):1165–1173.Google Scholar
Menke, A, Casagrande, S, Geiss, L, Cowie, CC. Prevalence of and trends in diabetes among adults in the United States, 1988–2012. JAMA. 2015; 314(10):1021–1029.CrossRefGoogle ScholarPubMed
Justice, JN, Niedernhofer, L, Robbins, PD, Aroda, VR, Espeland, MA, Kritchevsky, SB, et al. Development of clinical trials to extend healthy lifespan. Cardiovasc Endocrinol Metab. 2018; 7(4):80–83.Google Scholar
Milman, S, Barzilai, N. Dissecting the mechanisms underlying unusually successful human health span and life span. Cold Spring Harb Perspect Med. 2015; 6(1):a025098.CrossRefGoogle ScholarPubMed
Scudellari, M. Aging research: Blood to blood. Nature. 2015; 517(7535):426–429.Google Scholar
Lau, A, Kennedy, BK, Kirkland, JL, Tullius, SG. Mixing old and young: Enhancing rejuvenation and accelerating aging. J Clin Invest. 2019; 129(1): 4–11.Google Scholar
Liao, CY, Kennedy, BK. Mouse models and aging: Longevity and progeria. Curr Top Dev Biol. 2014; 109:249–285.Google Scholar
Kirkland, JL, Peterson, C. Healthspan, translation, and new outcomes for animal studies of aging. J Gerontol A Biol Sci Med Sci. 2009; 64(2):209–212.Google Scholar
Mannick, JB, Del Giudice, G, Lattanzi, M, Valiante, NM, Praestgaard, J, Huang, B, et al. mTOR inhibition improves immune function in the elderly. Sci Transl Med. 2014; 6(268):268ra179.Google Scholar
Richardson, A, Galvan, V, Lin, A-L, Oddo, S. How longevity research can lead to therapies for Alzheimer’s disease: The rapamycin story. Exp Gerontol. 2015; 68:51–58.CrossRefGoogle ScholarPubMed
Ness, KK, Kirkland, JL, Gramatges, MM, Wang, Z, Kundu, M, McCastlain, K, et al. Premature physiologic aging as a paradigm for understanding increased risk of adverse health across the lifespan of survivors of childhood cancer. J Clin Oncol. 2018; 36(21):2206–2215.CrossRefGoogle ScholarPubMed
Cupit-Link, MC, Kirkland, JL, Ness, KK, Armstrong, GT, Tchkonia, T, Le Brasseur, NK, et al. Biology of premature aging in survivors of cancer. ESMO Open. 2017; 2(5):e000250.CrossRefGoogle ScholarPubMed
High, KP, Akbar, AN, Nikolich-Zugich, J. Translational research in immune senescence: Assessing the relevance of current models. Seminars in Immunology. 2012; 24(5):373–382.Google Scholar
Butler, RN, Miller, RA, Perry, D, Cairns, BA, Williams, TF, Cassel, C, et al. New model of health promotion and disease prevention for the 21st century. BMJ. 2008; 337:a399.Google Scholar
Miller, RA. Extending life: Scientific prospects and political obstacles. Milbank Q. 2002; 80(1):155–174.Google Scholar
Newman, JC, Sokoloski, JL, Robbins, PD, Niedernhofer, LJ, Reed, MJ, Wei, J, et al. Creating the next generation of translational geroscientists. J Am Geriatr Soc. 2019; 67(9):1934–1939.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×