A proposed panel of biomarkers of healthy ageing

BMC Medicine

John C Mathers⁵  Diana Kuh⁴  Janet M Lord⁶  Ian J Deary³  Kay-Tee Khaw¹  Annie T Ginty²  Jack Nissan³  Rachel Cooper⁴  Jose Lara⁵ 

[1] University of Cambridge, Addenbrooke’s University Hospital, Cambridge, UK;School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK;Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK;MRC Unit for Lifelong Health and Ageing, MRC Unit for Lifelong Health and Ageing at UCL, 33 Bedford Place, London WC1B 5JU, UK;Human Nutrition Research Centre, Institute of Cellular Medicine and Newcastle University Institute for Ageing, Newcastle University, Biomedical Research Building, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK;MRC-ARUK Centre for Musculoskeletal Ageing Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

关键词: Immune function;    Endocrine function;    Musculoskeletal function;    Physiological function;    Cognitive function;    Physical capability;    Ageing;    Biomarkers;   

Others  :  1225012
DOI  :  10.1186/s12916-015-0470-9

 received in 2015-06-04, accepted in 2015-09-01,  发布年份 2015

【 摘 要 】

Background

There is no criterion reference for assessing healthy ageing and this creates difficulties when conducting and comparing research on ageing across studies. A cardinal feature of ageing is loss of function which translates into wide-ranging consequences for the individual and for family, carers and society. We undertook comprehensive reviews of the literature searching for biomarkers of ageing on five ageing-related domains including physical capability and cognitive, physiological and musculoskeletal, endocrine and immune functions. Where available, we used existing systematic reviews, meta-analyses and other authoritative reports such as the recently launched NIH Toolbox for assessment of neurological and behavioural function, which includes test batteries for cognitive and motor function (the latter described here as physical capability). We invited international experts to comment on our draft recommendations. In addition, we hosted an experts workshop in Newcastle, UK, on 22–23 October 2012, aiming to help capture the state-of-the-art in this complex area and to provide an opportunity for the wider ageing research community to critique the proposed panel of biomarkers.

Discussion

Here we have identified important biomarkers of healthy ageing classified as subdomains of the main areas proposed. Cardiovascular and lung function, glucose metabolism and musculoskeletal function are key subdomains of physiological function. Strength, locomotion, balance and dexterity are key physical capability subdomains. Memory, processing speed and executive function emerged as key subdomains of cognitive function. Markers of the HPA-axis, sex hormones and growth hormones were important biomarkers of endocrine function. Finally, inflammatory factors were identified as important biomarkers of immune function.

Summary

We present recommendations for a panel of biomarkers that address these major areas of function which decline during ageing. This biomarker panel may have utility in epidemiological studies of human ageing, in health surveys of older people and as outcomes in intervention studies that aim to promote healthy ageing. Further, the inclusion of the same common panel of measures of healthy ageing in diverse study designs and populations may enhance the value of those studies by allowing the harmonisation of surrogate endpoints or outcome measures, thus facilitating less equivocal comparisons between studies and the pooling of data across studies.

【 授权许可】

   
2015 Lara et al.

【 图 表 】

Fig. 1.

Fig. 2.

【 参考文献 】

• [1]Vaupel JW. Biodemography of human ageing. Nature. 2010; 464:536-542.
• [2]Langie SA, Lara J, Mathers JC. Early determinants of the ageing trajectory. Best Pract Res Clin Endocrinol Metab. 2012; 26:613-626.
• [3]A life course approach to healthy ageing. Oxford University Press, Oxford; 2014.
• [4]Strimbu K, Tavel JA. What are biomarkers? Curr Opin HIV AIDS. 2010; 5:463-466.
• [5]Comfort A. Test-battery to measure ageing-rate in man. Lancet. 1969; 2:1411-1414.
• [6]Johnson TE. Recent results: biomarkers of aging. Exp Gerontol. 2006; 41:1243-1246.
• [7]Engelfriet PM, Jansen EH, Picavet HS, Dolle ME. Biochemical markers of aging for longitudinal studies in humans. Epidemiol Rev. 2013; 35:132.
• [8]Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013; 153:1194-1217.
• [9]Baker GT, Sprott RL. Biomarkers of aging. Exp Gerontol. 1988; 23:223-239.
• [10]Butler RN, Sprott R, Warner H, Bland J, Feuers R, Forster M et al.. Aging: the reality: biomarkers of aging: from primitive organisms to humans. J Gerontol A: Biol Med Sci. 2004; 59:B560-B567.
• [11]Ingram DK. Key questions in developing biomarkers of aging. Exp Gerontol. 1988; 23:429-434.
• [12]Sprott RL. Biomarkers of aging and disease: introduction and definitions. Exp Gerontol. 2010; 45:2-4.
• [13]Martin-Ruiz C, Jagger C, Kingston A, Collerton J, Catt M, Davies K et al.. Assessment of a large panel of candidate biomarkers of ageing in the Newcastle 85+ study. Mech Ageing Dev. 2011; 132:496-502.
• [14]Gershon RC, Wagster MV, Hendrie HC, Fox NA, Cook KF, Nowinski CJ. NIH toolbox for assessment of neurological and behavioral function. Neurology. 2013; 80:S2-S6.
• [15]Lara J, Godfrey A, Evans E, Heaven B, Brown LJ, Barron E et al.. Towards measurement of the Healthy Ageing Phenotype in lifestyle-based intervention studies. Maturitas. 2013; 76:189-199.
• [16]Steptoe A, Deaton A, Stone AA. Subjective wellbeing, health, and ageing. Lancet. 2014; 385:640.
• [17]Guidelines for biomarkers of healthy ageing. http://www. mrc.ac.uk/documents/pdf/biomarkers-of-healthy-ageing/ webcite
• [18]Cooper R, Kuh D, Hardy R. Objectively measured physical capability levels and mortality: systematic review and meta-analysis. BMJ. 2010; 341:c4467.
• [19]Cooper R, Hardy R, Aihie Sayer A, Ben-Shlomo Y, Birnie K, Cooper C et al.. Age and gender differences in physical capability levels from mid-life onwards: the harmonisation and meta-analysis of data from eight UK cohort studies. PLoS One. 2011; 6:e27899.
• [20]Cooper R, Strand BH, Hardy R, Patel KV, Kuh D. Physical capability in mid-life and survival over 13 years of follow-up: British birth cohort study. BMJ. 2014; 348:g2219.
• [21]Cooper R, Kuh D, Cooper C, Gale CR, Lawlor DA, Matthews F et al.. Objective measures of physical capability and subsequent health: a systematic review. Age Ageing. 2011; 40:14-23.
• [22]Cooper R, Stafford M, Hardy R, Aihie Sayer A, Ben-Shlomo Y, Cooper C et al.. Physical capability and subsequent positive mental wellbeing in older people: findings from five HALCyon cohorts. Age (Dordr). 2014; 36:445-456.
• [23]Physiological basis of aging and geriatrics. 4th ed. Informa, New York, NY; 2007.
• [24]Singh-Manoux A, Dugravot A, Kauffmann F, Elbaz A, Ankri J, Nabi H et al.. Association of lung function with physical, mental and cognitive function in early old age. Age (Dordr). 2011; 33:385-392.
• [25]Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, Halsey J et al.. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet. 2009; 373:1083-1096.
• [26]Sun Q, Townsend MK, Okereke OI, Franco OH, Hu FB, Grodstein F. Adiposity and weight change in mid-life in relation to healthy survival after age 70 in women: prospective cohort study. BMJ. 2009; 339:b3796.
• [27]Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002; 360:1903-1913.
• [28]Clark CE, Taylor RS, Shore AC, Ukoumunne OC, Campbell JL. Association of a difference in systolic blood pressure between arms with vascular disease and mortality: a systematic review and meta-analysis. Lancet. 2012; 379:905-914.
• [29]Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J et al.. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet. 2007; 370:1829-1839.
• [30]Matthias B, Ignacio F-G, John JY, Paul JK, Elie AA, Ping W et al.. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ. 2009; 338:b92.
• [31]Salthouse T. Consequences of age-related cognitive declines. Annu Rev Psychol. 2012; 63:201-226.
• [32]Salthouse TA. When does age-related cognitive decline begin? Neurobiol Aging. 2009; 30:507-514.
• [33]Singh-Manoux A, Kivimaki M, Glymour MM, Elbaz A, Berr C, Ebmeier KP et al.. Timing of onset of cognitive decline: results from Whitehall II prospective cohort study. BMJ. 2012; 344:d7622.
• [34]Craik FIM, Bialystok E. Cognition through the lifespan: mechanisms of change. Trends Cogn Sci. 2006; 10:131-138.
• [35]Salthouse TA. Aging and measures of processing speed. Biol Psychol. 2000; 54:35-54.
• [36]Deary IJ, Der G. Reaction time, age, and cognitive ability: longitudinal findings from age 16 to 63 years in representative population samples. Aging Neuropsychol Cognit. 2005; 12:187-215.
• [37]Shipley BA, Der G, Taylor MD, Deary IJ. Association between mortality and cognitive change over 7 years in a large representative sample of UK residents. Psychosom Med. 2007; 69:640-650.
• [38]Pause BM, Zlomuzica A, Kinugawa K, Mariani J, Pietrowsky R, Dere E. Perspectives on episodic-like and episodic memory. Front Behav Neurosci. 2013; 7:33.
• [39]Murray C, Pattie A, Starr JM, Deary IJ. Does cognitive ability predict mortality in the ninth decade? The Lothian Birth Cohort 1921. Intelligence. 2012; 40:490-498.
• [40]Salthouse TA. Major issues in cognitive aging. Oxford University Press, Oxford; 2010.
• [41]Mazat L, Lafont S, Berr C, Debuire B, Tessier J-F, Dartigues J-F et al.. Prospective measurements of dehydroepiandrosterone sulfate in a cohort of elderly subjects: Relationship to gender, subjective health, smoking habits, and 10-year mortality. Proc Natl Acad Sci. 2001; 98:8145-8150.
• [42]MacLean C, Newberry S, Maglione M, McMahon M, Ranganath V, Suttorp M et al.. Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Ann Intern Med. 2008; 148:197-213.
• [43]Farquhar CM, Marjoribanks J, Lethaby A, Lamberts Q, Suckling JA. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2005; 3:CD004143.
• [44]Steptoe A, Kivimaki M. Stress and cardiovascular disease. Nat Rev Cardiol. 2012; 9:360-370.
• [45]Rosmond R, Wallerius S, Wanger P, Martin L, Holm G, Bjorntorp P. A 5-year follow-up study of disease incidence in men with an abnormal hormone pattern. J Intern Med. 2003; 254:386-390.
• [46]Whisler RL, Newhouse YG. Immunosenescence of the human B cell system: impaired activation/proliferation in response to autologous monocytes pulsed with Staph protein A and the effects of interleukins 1 and 2 compared to interferon. Lymphokine Res. 1985; 4:331-337.
• [47]Handbook on immunosenescence: basic understanding and clinical applications. Springer, Berlin; 2009.
• [48]Pawelec G, Ferguson FG, Wikby A. The SENIEUR protocol after 16 years. Mech Ageing Dev. 2001; 122:132-134.
• [49]Wikby A, Månsson I, Johansson B, Strindhall J, Nilsson S. The immune risk profile is associated with age and gender: findings from three Swedish population studies of individuals 20–100 years of age. Biogerontology. 2008; 9:299-308.
• [50]Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E et al.. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000; 908:244-254.
• [51]Verghese J, Holtzer R, Oh-Park M, Derby CA, Lipton RB, Wang C. Inflammatory markers and gait speed decline in older adults. J Gerontol A Biol Sci Med Sci. 2011; 66:1083-1089.
• [52]Doty RL. Olfactory dysfunction in Parkinson disease. Nat Rev Neurol. 2012; 8:329-339.
• [53]Pinto JM, Wroblewski KE, Kern DW, Schumm LP, McClintock MK. Olfactory dysfunction predicts 5-year mortality in older adults. PLoS One. 2014; 9:e107541.
• [54]Belsky DW, Caspi A, Houts R, Cohen HJ, Corcoran DL, Danese A et al.. Quantification of biological aging in young adults. Proc Natl Acad Sci U S A. 2015; 112:E4104.
• [55]Burkle A, Moreno-Villanueva M, Bernhard J, Blasco M, Zondag G, Hoeijmakers JH et al.. MARK-AGE biomarkers of ageing. Mechanisms Ageing Dev. 2015.
• [56]Levine ME. Modeling the rate of senescence: can estimated biological age predict mortality more accurately than chronological age? J Gerontol A Biol Sci Med Sci. 2013; 68:667-674.
• [57]Howlett SE, Rockwood MR, Mitnitski A, Rockwood K. Standard laboratory tests to identify older adults at increased risk of death. BMC Med. 2014; 12:171. BioMed Central Full Text
• [58]Mitnitski A, Collerton J, Martin-Ruiz C, Jagger C, von Zglinicki T, Rockwood K et al.. Age-related frailty and its association with biological markers of ageing. BMC Med. 2015; 13:161. BioMed Central Full Text