Ageing Abstracts 7, Biomarkers II


Biomarkers of aging.
            (Baker and Sprott, 1988) Download
This article presents a conceptual discussion of some aspects involved in biomarkers of aging. A biomarker of aging is a biological parameter of an organism that either alone or in some multivariate composite will, in the absence of disease, better predict functional capability at some late age than will chronological age. The reasons for undertaking biomarker research, criteria for putative biomarkers, measurement and assessment of putative biomarkers, and the new initiative by the National Institute on Aging in biomarker research are discussed.

Blood-Borne Biomarkers of Mortality Risk: Systematic Review of Cohort Studies.
            (Barron et al., 2015) Download
BACKGROUND: Lifespan and the proportion of older people in the population are increasing, with far reaching consequences for the social, political and economic landscape. Unless accompanied by an increase in health span, increases in age-related diseases will increase the burden on health care resources. Intervention studies to enhance healthy ageing need appropriate outcome measures, such as blood-borne biomarkers, which are easily obtainable, cost-effective, and widely accepted. To date there have been no systematic reviews of blood-borne biomarkers of mortality. AIM: To conduct a systematic review to identify available blood-borne biomarkers of mortality that can be used to predict healthy ageing post-retirement. METHODS: Four databases (Medline, Embase, Scopus, Web of Science) were searched. We included prospective cohort studies with a minimum of two years follow up and data available for participants with a mean age of 50 to 75 years at baseline. RESULTS: From a total of 11,555 studies identified in initial searches, 23 fulfilled the inclusion criteria. Fifty-one blood borne biomarkers potentially predictive of mortality risk were identified. In total, 20 biomarkers were associated with mortality risk. Meta-analyses of mortality risk showed significant associations with C-reactive protein (Hazard ratios for all-cause mortality 1.42, p<0.001; Cancer-mortality 1.62, p<0.009; CVD-mortality 1.31, p = 0.033), N Terminal-pro brain natriuretic peptide (Hazard ratios for all-cause mortality 1.43, p<0.001; CHD-mortality 1.58, p<0.001; CVD-mortality 1.67, p<0.001) and white blood cell count (Hazard ratios for all-cause mortality 1.36, p = 0.001). There was also evidence that brain natriuretic peptide, cholesterol fractions, erythrocyte sedimentation rate, fibrinogen, granulocytes, homocysteine, intercellular adhesion molecule-1, neutrophils, osteoprotegerin, procollagen type III aminoterminal peptide, serum uric acid, soluble urokinase plasminogen activator receptor, tissue inhibitor of metalloproteinases 1 and tumour necrosis factor receptor II may predict mortality risk. There was equivocal evidence for the utility of 14 biomarkers and no association with mortality risk for CD40 ligand, cortisol, dehydroepiandrosterone, ferritin, haemoglobin, interleukin-12, monocyte chemoattractant protein 1, matrix metalloproteinase 9, myelopereoxidase, P-selectin, receptor activator of nuclear factor KappaB ligand, sex hormone binding globulin, testosterone, transferrin, and thyroid stimulating hormone and thyroxine. CONCLUSIONS: Twenty biomarkers should be prioritised as potential predictors of mortality in future studies. More studies using standardised protocols and reporting methods, and which focus on mortality rather than risk of disease or health status as an outcome, are needed.

Biochemical markers of aging for longitudinal studies in humans.
            (Engelfriet et al., 2013) Download
Much progress has been made in the past decades in unraveling the mechanisms that are responsible for aging. The discovery that particular gene mutations in experimental species such as yeast, flies, and nematodes are associated with longevity has led to many important insights into pathways that regulate aging processes. However, extrapolating laboratory findings in experimental species to knowledge that is valid for the complexity of human physiology remains a major challenge. Apart from the restricted experimental possibilities, studying aging in humans is further complicated by the development of various age-related diseases. The availability of a set of biomarkers that really reflect underlying aging processes would be of much value in disentangling age-associated pathology from specific aging mechanisms. In this review, we survey the literature to identify promising biochemical markers of aging, with a particular focus on using them in longitudinal studies of aging in humans that entail repeated measurements on easily obtainable material, such as blood samples. Our search strategy was a 2-pronged approach, one focused on general mechanisms of aging and one including studies on clinical biomarkers of age-related diseases.

Endocrine markers of aging.
            (Halter, 1988) Download
Sophisticated methods available to quantitate hormone secretion and hormone action provide opportunities to identify potential endocrine biomarkers of aging. However, there are many challenges facing the investigator who wishes to establish an endocrine biomarker. Circulating levels of many hormones fluctuate on a circadian rhythm, and a variety of other short-term fluctuations may occur. Hormone secretion is generally tightly regulated and often affected by multiple, redundant feedback mechanisms. Interpretation of circulating hormone levels must also take into account factors affecting hormone metabolism and degradation which may be influenced by age. The rate of hormone secretion and circulating hormone levels are related to the sensitivity to hormone action by feedback control mechanisms. Thus interpretation of potential circulating endocrine markers of aging must take into account changes in sensitivity to that hormone as well.

Biomarkers for cognitive aging part I: telomere length, blood pressure and cognition among individuals with hypertension.
            (Insel et al., 2012a) Download
Chronological age is used as a marker for age-associated changes in cognitive function. However, there is great interindividual variability in cognitive ability among people of the same age. Physiological age rather than chronological age should be more closely associated with age-related cognitive changes because these changes are not universal and are likely dependent on several factors in addition to the number of years lived. Cognitive function is associated with successful self-management, and a biological marker that reflects physiological age and is associated with cognitive function could be used to identify risk for failure to self-manage. The purpose of this study was to investigate the association between telomere length, a known biomarker of age; blood pressure; cognitive assessments; and adherence to antihypertensive medication among community-dwelling middle-aged and older adults. The authors administered a battery of cognitive assessments to 42 participants (M = 69 years of age), collected blood samples, and isolated peripheral blood mononuclear leukocytes for genomic DNA. The authors determined relative telomere length using Cawthon's method for real-time quantitative polymerase chain reaction (RT-qPCR) and measured medication adherence using an electronic medication monitoring system (MEMS by Aardex) over 8 weeks. Findings indicate that telomere length was inversely associated with systolic blood pressure (r = -.38, p < .01) and diastolic blood pressure (r = -.42, p < .01) but not with cognitive assessments or adherence. The authors discuss the nonsignificant findings between telomere length and cognitive assessments including the potential modifying role of gender.

Biomarkers for cognitive aging part II: oxidative stress, cognitive assessments, and medication adherence.
            (Insel et al., 2012b) Download
The purpose of this study was to further examine potential biomarkers of cognitive aging by looking at the associations among oxidative stress, cognitive abilities, and medication adherence in a community-based sample of middle-aged and older adults (n = 42; mean age = 69 years) prescribed at least one medication for hypertension. In addition to measures described in Part I, "Biomarkers for Cognitive Aging," a 12-hr urine collection for F(2)-isoprostanes served as an indicator of oxidative stress. Participants completed a battery of cognitive assessments and 8 weeks of electronic medication monitoring for adherence to one antihypertensive agent. Oxidative stress was significantly associated with logical memory, immediate (r = -.38, p < .01) and delayed recall (r = -.42, p < .01), and recognition memory (r = -.42, p < .01) from the Wechsler Memory Scale III, number of perseveration errors (r = .26, p < .05) and categories achieved (r = -.26, p < .01) on the Wisconsin Card Sorting Test (WSCT), and medication adherence (r = -.34, p <.05). Findings indicate that a biomarker of oxidative stress, F(2)-isoprostanes corrected for vitamin E, is significantly associated with cognitive measures and a functional outcome.

Constitutional genetic markers of aging.
            (Martin, 1988) Download
Constitutional genetic markers of aging can be defined as members of that subset of genes that modulate the times of onset and/or the rates of progression of one or more of the processes of aging, or the response of the target cells, tissues and organisms to a particular process. These genetic factors are classified into: (1) those that control changes in structure and function that may be universally expressed in aging organisms or that are expressed in large taxonomic groups of organisms ("public markers") and (2) those that control changes that are species specific or that reflect polymorphisms or mutations within a species ("private markers"). Both spontaneous and experimentally induced genetic variation can identify and characterize such genetic elements. Recommendations for implementing such a program of research include (1) particularization of the aging phenotype, (2) further development of nonmammalian models amenable to genetic analysis, (3) systematic search for relevant spontaneous mutations in Mus musculus, (4) utilization of recombinant inbred, chimeric, transgenic and interspecific mice and (5) investigations of genetic concomitants of speciation.

Assessment of a large panel of candidate biomarkers of ageing in the Newcastle 85+ study.
            (Martin-Ruiz et al., 2011) Download
Sensitive and specific biomarkers of ageing are needed to evaluate interventions to extend health span. However, there is growing evidence that information provided by candidate biomarkers may change with age itself. Little is yet known about the value of candidate biomarkers in those over 85 years, currently the fastest growing population sub-group in many countries. This study assessed a large panel of candidate biomarkers in a cohort of 85 years old by studying comparative associations with health status. Using a cross-sectional sample of 852 individuals aged 85, we performed uni- and multi-variable analyses of associations between 74 candidate biomarkers and 4 health-status measures: viz. multi-morbidity, cognitive impairment, disability and proximity to death as measured by mortality within 1.5 years. We defined as most informative any measures that were significantly associated with at least two of the health-status measures in multivariable analyses in this age group. 10 out of 74 tested candidates fulfilled this criterion, while several proposed biomarkers of ageing, notably inflammation and immune risk markers and telomere length, did not. As future data accrues on health outcomes within the cohort, it will become possible also to evaluate the predictive value of these and others of the candidate biomarkers.

A method for identifying biomarkers of aging and constructing an index of biological age in humans.
            (Nakamura and Miyao, 2007) Download
This study was conducted to identify biomarkers of aging and to construct an index of biological age in humans. Healthy adult men (n = 86) who had received an annual health examination from 1992 through 1998 were studied. From 29 physiological variables, five variables (forced expiratory volume in 1 second, systolic blood pressure, hematocrit, albumin, blood urea nitrogen) were selected as candidate biomarkers of aging. Five candidate biomarkers expressed substantial covariance along one principal component. The first principal component obtained from a principal component analysis was used to calculate biological age scores (BAS). Individual BAS showed high longitudinal stability of age-related changes. Age-related changes of BAS are characterized by three components: age, peak functional capacity, and aging rate. A logistic regression analysis suggested that aging rate was influenced by environmental factors, but peak functional capacity was almost independent of environmental factors.

Mitochondrial enzyme activities as biochemical markers of aging.
            (Navarro, 2004) Download
The decrease of neurological performance in normal aging is directly related to brain oxidative stress and inversely related to lifespan. Male mice lifespan was increased by 8-10% (median and maximal lifespan, respectively) in mice with high spontaneous neurological activity, by 21-15% after moderate exercise; and by 25-20% after supplementation with vitamin E. Oxidative stress markers, TBARS and protein carbonyl content, were found increased on aging; a higher content of oxidation products is considered an effective aging factor, specially in the brain, with a majority of postmitotic cells. Mitochondrial enzyme activities, mitochondrial nitric oxide synthase (mtNOS), NADH dehydrogenase and cytochrome oxidase, behaved as markers of brain aging. The decrease in enzyme activities was directly related to the content of oxidation products and to the loss of neurological function in aged mice, this latter was determined in the tighrope and the T-maze tests. The above mentioned conditions that increased mice lifespan were effective to decrease the level of oxidative stress markers, and to retard the decreases in mitochondrial enzyme activities and neurological function associated to aging. The activities of mtNOS, NADH dehydrogenase and cytochrome oxidase may be used as indicators of the effectiveness of antiaging treatments.

Serum insulin-like growth factor 1 and facial ageing: high levels associate with reduced skin wrinkling in a cross-sectional study.
            (Noordam et al., 2013) Download
BACKGROUND: Insulin-like growth factor (IGF)-1 is a growth factor that can influence fibroblast functioning, with effects including the inhibition of collagenases and the induction of collagen expression. OBJECTIVES: To assess whether serum IGF-1, IGF-binding protein (IGFBP)3 and the ratio between IGF-1 and IGFBP3, as a measure of IGF-1 bioavailability, are associated with facial ageing and skin wrinkling. METHODS: From a random sample comprising 617 subjects from the Leiden Longevity Study, perceived age and skin wrinkling were assessed from facial photographs, and IGF-1 and IGFBP3 were measured in serum. The associations were assessed using linear regression models, adjusted for chronological age, sex, body mass index, smoking and sun exposure. RESULTS: Across tertiles of the ratio of IGF-1 to IGFBP3, and after adjusting for all potential confounding factors, the mean perceived age decreased from 60.6 years in the lowest tertile to 59.5 years in the highest (P = 0.045). Similarly, the mean skin wrinkling grade decreased from 4.8 in the lowest tertile to 4.5 in the highest (P = 0.011). Adding skin wrinkling as a covariate in the analysis between IGF-1 and perceived age diminished this association. CONCLUSIONS: This study demonstrates that a higher ratio of IGF-1 to IGFBP3 associates with a lower perceived age, via its association with reduced skin wrinkling. Whether high IGF-1 levels actually delay the accumulation of skin wrinkling now needs investigating.

Healthy ageing, but what is health?
            (Rattan, 2013) Download
Ageing occurs in spite of complex pathways of maintenance and repair. There is no "enemy within", which has the specific evolution-selected function to cause ageing and death. This understanding of ageing should transform our approach towards interventions from therapeutic "anti-ageing" to maintaining health. But what is health? Ideally, health is a state of complete physical and mental independence in activities of daily living. But in pragmatic terms, health is a state of adequate physical and mental independence in activities of daily living. In order to identify a set of measurable, evidence-based and demonstratable parameters of health, robustness and resilience at various levels, the concept of homeodynamic space can be a useful one. Age-related health problems for which there are no clear-cut causative agents, except the complex process of ageing, may be better tackled by focusing on health mechanisms and their maintenance, rather than disease management and treatment. Continuing the disease-oriented research approaches are economically, socially and psychologically unsustainable as compared with health-oriented and preventive strategies, such as hormesis. Supporting health-oriented research is the urgency of our time.

Clinical oxidation parameters of aging.
            (Voss and Siems, 2006) Download
Aging is a complex progressive physiological alteration of the organism which ultimately leads to death. During the whole life a human being is confronted with oxidative stress. To measure how this oxidative stress is developing during the aging process and how it changes the cellular metabolism several substances have been pronounced as biomarkers including lipid peroxidation (LPO) products, protein oxidation products, antioxidative acting enzymes, minerals, vitamins, glutathione, flavonoids, bilirubin and uric acid (UA). But none of them could develop to the leading one which is accepted by the whole scientific community to determine the life expectancy of the individual person or biological age or age-related health status. Further there are many conflicting data about the changes of each single biomarker during the aging process. There are so many different influences acting on the concentration or activity of single substances or single enzymes that it is not possible to measure only one clinical marker and determine how healthy an individual is or to predict the life expectancy of the corresponding person. Therefore, always a set or pattern of clinical biomarkers should be used to determine the oxidation status of the person. This set should include at least one marker for the LPO, the protein oxidation and the total antioxidative status and ideally also one for DNA damages.



Baker, GT 3rd and RL Sprott (1988), ‘Biomarkers of aging.’, Exp Gerontol, 23 (4-5), 223-39. PubMedID: 3058488
Barron, E, et al. (2015), ‘Blood-Borne Biomarkers of Mortality Risk: Systematic Review of Cohort Studies.’, PLoS One, 10 (6), e0127550. PubMedID: 26039142
Engelfriet, PM, et al. (2013), ‘Biochemical markers of aging for longitudinal studies in humans.’, Epidemiol Rev, 35 132-51. PubMedID: 23382477
Halter, JB (1988), ‘Endocrine markers of aging.’, Exp Gerontol, 23 (4-5), 377-85. PubMedID: 3058493
Insel, KC, et al. (2012a), ‘Biomarkers for cognitive aging part I: telomere length, blood pressure and cognition among individuals with hypertension.’, Biol Res Nurs, 14 (2), 124-32. PubMedID: 21586494
Insel, KC, et al. (2012b), ‘Biomarkers for cognitive aging part II: oxidative stress, cognitive assessments, and medication adherence.’, Biol Res Nurs, 14 (2), 133-38. PubMedID: 21586493
Martin-Ruiz, C, et al. (2011), ‘Assessment of a large panel of candidate biomarkers of ageing in the Newcastle 85+ study.’, Mech Ageing Dev, 132 (10), 496-502. PubMedID: 21864562
Martin, GM (1988), ‘Constitutional genetic markers of aging.’, Exp Gerontol, 23 (4-5), 257-70. PubMedID: 3058489
Nakamura, E and K Miyao (2007), ‘A method for identifying biomarkers of aging and constructing an index of biological age in humans.’, J Gerontol A Biol Sci Med Sci, 62 (10), 1096-105. PubMedID: 17921421
Navarro, A (2004), ‘Mitochondrial enzyme activities as biochemical markers of aging.’, Mol Aspects Med, 25 (1-2), 37-48. PubMedID: 15051315
Noordam, R, et al. (2013), ‘Serum insulin-like growth factor 1 and facial ageing: high levels associate with reduced skin wrinkling in a cross-sectional study.’, Br J Dermatol, 168 (3), 533-38. PubMedID: 23363376
Rattan, SI (2013), ‘Healthy ageing, but what is health?’, Biogerontology, 14 (6), 673-77. PubMedID: 23852043
Voss, P and W Siems (2006), ‘Clinical oxidation parameters of aging.’, Free Radic Res, 40 (12), 1339-49. PubMedID: 17090423