Low mitochondrial DNA content associates with familial longevity: the Leiden Longevity Study

Long-lived individuals delay aging and age-related diseases like diabetes, hypertension, and cardiovascular disease. The exact underlying mechanisms are largely unknown, but enhanced mitochondrial biogenesis and preservation of mitochondrial function have been suggested to explain healthy ageing. We investigated whether individuals belonging to long-lived families have altered mitochondrial DNA (mtDNA) content, as a biomarker of mitochondrial biogenesis and measured expression of genes regulating mitochondrial biogenesis. mtDNA and nuclear DNA (nDNA) levels were measured in blood samples from 2,734 participants from the Leiden Longevity Study: 704 nonagenarian siblings, 1,388 of their middle-aged offspring and 642 controls. We confirmed a negative correlation of mtDNA content in blood with age and a higher content in females. The middle-aged offspring had, on average, lower levels of mtDNA than controls and the nonagenarian siblings had an even lower mtDNA content (mtDNA/nDNA ratio = 0.744 ± 0.065, 0.767 ± 0.058 and 0.698 ± 0.074, respectively; p_{controls-offspring} = 3.4 × 10⁻¹², p_{controls-nonagenarians} = 6.5 × 10⁻⁶), which was independent of the confounding effects of age and gender. Subsequently, we examined in a subset of the study the expression in blood of two genes regulating mitochondrial biogenesis, YY1 and PGC-1α. We found a positive association of YY1 expression and mtDNA content in controls. The observed absence of such an association in the offspring suggests an altered regulation of mitochondrial biogenesis in the members of long-lived families. In conclusion, in this study, we show that mtDNA content decreases with age and that low mtDNA content is associated with familial longevity. Our data suggest that preservation of mitochondrial function rather than enhancing mitochondrial biogenesis is a characteristic of long-lived families.     

Lipid metabolism in long-lived families: the Leiden Longevity Study

Mechanisms underlying the variation in human life expectancy are largely unknown, but lipid metabolism and especially lipoprotein size was suggested to play an important role in longevity. We have performed comprehensive lipid phenotyping in the Leiden Longevity Study (LLS). By applying multiple logistic regression analysis we tested for the first time the effects of parameters in lipid metabolism (i.e., classical serum lipids, lipoprotein particle sizes, and apolipoprotein E levels) on longevity independent of each other. Parameters in lipid metabolism were measured in offspring of nonagenarian siblings from 421 families of the LLS (n = 1,664; mean age, 59 years) and in the partners of the offspring as population controls (n = 711; mean age, 60 years). In the initial model, where lipoprotein particles sizes, classical serum lipids and apolipoprotein E were included, offspring had larger low-density lipoprotein (LDL) particle sizes (p = 0.017), and lower triglyceride levels (p = 0.026), indicating that they displayed a more beneficial lipid profile. After backwards regression only LDL size (p = 0.014) and triglyceride levels (p = 0.05) were associated with offspring from long-lived families. Sex-specific backwards regression analysis revealed that LDL particle sizes were associated with male longevity (increase in log odds ratio (OR) per unit = 0.21; p = 0.023). Triglyceride levels (decrease OR per unit = 0.22; p = 0.01), but not LDL particle size, were associated with female longevity. Due to the analysis of a comprehensive lipid profile, we confirmed an important role of lipid metabolism in human longevity, with LDL size and triglyceride levels as major predicting factors.     

Favorable Glucose Tolerance and Lower Prevalence of Metabolic Syndrome in Offspring without Diabetes Mellitus of Nonagenarian Siblings: The Leiden Longevity Study

OBJECTIVES: To explore measures of metabolic syndrome and glucose metabolism in families with exceptional longevity. DESIGN: Case–control study. SETTING: A university hospital in Leiden, the Netherlands. PARTICIPANTS: One hundred twenty‐one offspring of nonagenarian siblings, who were enriched for familial factors promoting longevity, and 113 of their partners. No subject had diabetes mellitus. MEASUREMENTS: Prevalence of metabolic syndrome was determined according to the criteria of the Third Report of the National Cholesterol Education Program. Glucose tolerance was assessed according to a 2‐hour oral glucose tolerance test. RESULTS: The offspring of nonagenarians siblings had a lower prevalence of metabolic syndrome (P=.03), similar body composition, lower mean fasting blood glucose levels (4.99 vs 5.16 mmol/L; P=.01), lower mean fasting insulin levels (5.81 vs 6.75 mU/L; P=.04), a higher mean homeostasis model assessment of insulin sensitivity (0.78 vs 0.65; P=.02), and a more‐favorable glucose tolerance (mean area under the receiver operating characteristic curve for glucose (13.2 vs 14.3; P=.007) than their partners. No significant differences were observed between the offspring and their partners in β‐cell function (insulogenic index 13.6 vs 12.5; P=.38). CONCLUSION: Despite similar body composition, the offspring of nonagenarian siblings showed a lower prevalence of metabolic syndrome and better glucose tolerance than their partners, centralizing the role of favorable glucose metabolism in familial longevity.     

Nonagenarian Siblings and Their Offspring Display Lower Risk of Mortality and Morbidity than Sporadic Nonagenarians: The Leiden Longevity Study

OBJECTIVES: To compare the risk of mortality of nonagenarian siblings with that of sporadic nonagenarians (not selected on having a nonagenarian sibling) and to compare the prevalence of morbidity in their offspring with that of the offsprings' partners.
DESIGN: Longitudinal (mortality risk) and cross-sectional (disease prevalence).
SETTING: Nationwide sample.
PARTICIPANTS: The Leiden Longevity Study consists of 991 nonagenarian siblings derived from 420 Caucasian families, 1,365 of their offspring, and 621 of the offsprings' partners. In the Leiden 85-plus Study, 599 subjects aged 85 were included, of whom 275 attained the age of 90 (sporadic nonagenarians).
MEASUREMENTS: All nonagenarian siblings and sporadic nonagenarians were followed for mortality (with a mean±standard deviation follow-up time of 2.7±1.4 years and 3.0±1.5 years, respectively). Information on medical history and medication use was collected for offspring and their partners.
RESULTS: Nonagenarian siblings had a 41% lower risk of mortality ( P <.001) than sporadic nonagenarians. The offspring of nonagenarian siblings had a lower prevalence of myocardial infarction (2.4% vs 4.1%, P =.03), hypertension (23.0% vs 27.5%, P =.01), diabetes mellitus (4.4% vs 7.6%, P =.004), and use of cardiovascular medication (23.0% vs 28.9%, P =.003) than their partners.
CONCLUSION: The lower mortality rate of nonagenarian siblings and lower prevalence of morbidity in their middle-aged offspring reinforce the notion that resilience against disease and death have similar underlying biology that is determined by genetic or familial factors.     

Handgrip strength at midlife and familial longevity

Low handgrip strength has been linked with premature mortality in diverse samples of middle-aged and elderly subjects. The value of handgrip strength as marker of "exceptional" human longevity has not been previously explored. We postulated that the genetic influence on extreme survival might also be involved in the muscular strength determination pathway. Therefore, the objective of this study was to assess the muscle strength in a sample of middle-aged adults who are genetically enriched for exceptional survival and comparing them to a control group. We included 336 offspring of the nonagenarian from the Leiden Longevity Study who were enriched for heritable exceptional longevity, and 336 of their partners were used as controls. The Leiden Longevity study was a prospective follow up study of long-living siblings pairs together with their offspring and their partners. Handgrip strength was used as a proxy for overall muscle strength. No significant difference in handgrip strength was seen between the offspring of the nonagenarian and their partners after adjustment for potential confounders including body compositions, sum score of comorbidities, medication use, smoking and alcohol history. The main determinants of midlife handgrip strength were age, gender, total body percentage fat and relative appendicular lean mass. Although midlife handgrip strength has previously been shown to be an important prognostic indicator of survival, it is not a marker of exceptional familial longevity in middle-aged adults. This finding suggests that genetic component of susceptibility to extreme survival is likely to be separate from that of muscular strength.     

Association of healthy aging with parental longevity

Various measures incorporated in geriatric assessment have found their way into frailty indices (FIs), which have been used as indicators of survival/mortality and longevity. Our goal is to understand the genetic basis of healthy aging to enhance its evidence base and utility. We constructed a FI as a quantitative measure of healthy aging and examined its characteristics and potential for genetic analyses. Two groups were selected from two separate studies. One group (OLLP for offspring of long-lived parents) consisted of unrelated participants at least one of whose parents was age 90 or older, and the other group of unrelated participants (OSLP for offspring of short-lived parents), both of whose parents died before age 76. FI₃₄ scores were computed from 34 common health variables and compared between the two groups. The FI₃₄ was better correlated than chronological age with mortality. The mean FI₃₄ value of the OSLP was 31 % higher than that of the OLLP (P = 0.0034). The FI₃₄ increased exponentially, at an instantaneous rate that accelerated 2.0 % annually in the OLLP (P = 0.024) and 2.7 % in the OSLP (P < < 0.0001) consequently yielding a 63 % larger accumulation in the latter group (P = 0.0002). The results suggest that accumulation of health deficiencies over the life course is not the same in the two groups, likely due to inheritance related to parental longevity. Consistent with this, sib pairs were significantly correlated regarding FI₃₄ scores, and heritability of the FI₃₄ was estimated to be 0.39. Finally, hierarchical clustering suggests that the OLLP and OSLP differ in their aging patterns. Variation in the FI₃₄ is, in part, due to genetic variation; thus, the FI₃₄ can be a phenotypic measure suitable for genetic analyses of healthy aging.

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Low computed tomography coronary artery calcium scores in familial longevity: the Leiden Longevity Study

Offspring of long-lived parents have a low prevalence of cardiovascular disease in middle age. The purposes of this study were to investigate calcium scores in offspring as compared to controls and to determine the influence of cardiovascular risk factors. CT coronary artery calcium score was measured in offspring of long-lived families (n = 244, 125 males) and their partners (n = 223, 96 males) who served as controls. Calcium scores were analyzed separately for sexes. Subjects were grouped by very low calcium score ≤10 and scores above 10. Nonparametric Mann-Whitney test, chi-squared tests, and logistic regression analyses were performed to determine the association between calcium scores, familial longevity, and cardiovascular risk factors. More offspring of long-lived parents had lower calcium scores than controls. In men, 34 % of offspring had score ≤10 versus 21 % of controls (odds ratio (OR) and 95 % confidence interval (CI) 2.0, 1.08–3.7, p = 0.028). In women, 70 % of offspring had score ≤10 versus 54 % of controls (OR 1.9, 95 % CI 1.13–3.4, p = 0.019). Differences remained significant after correction for age (men, p = 0.043 and women, p = 0.003) and further correction for major risk factors in women, indicating genetic influence for lower calcium scores. In men, the association was found to be influenced by cardiovascular risk factors. Men and women with a familial propensity to become long-lived have lower coronary artery calcium scores than controls. Low scores may indicate a younger biologic arterial age associated with a low risk for incident cardiovascular disease.     

Association of exceptional parental longevity and physical function in aging

Offspring of parents with exceptional longevity (OPEL), who are more likely to carry longevity-associated genotypes, may age more successfully than offspring of parents with usual survival (OPUS). Maintenance of physical function is a key attribute of successful aging. While many genetic and non-genetic factors interact to determine physical phenotype in aging, examination of the contribution of exceptional parental longevity to physical function in aging is limited. The LonGenity study recruited a relatively genetically homogenous cohort of Ashkenazi Jewish (AJ) adults age 65 and older, who were defined as either OPEL (having at least one parent who lived to age 95 or older) or OPUS (neither parent survived to age 95). Subjective and objective measures of physical function were compared between the two groups, accounting for potential confounders. Of the 893 LonGenity subjects, 365 were OPEL and 528 were OPUS. OPEL had better objective and subjective measures of physical function than OPUS, especially on unipedal stance (p = 0.009) and gait speed (p = 0.002). Results support the protective role of exceptional parental longevity in preventing decline in physical function, possibly via genetic mechanisms that should be further explored.     

Modulation of human longevity by SIRT3 single nucleotide polymorphisms in the prospective study “Treviso Longeva (TRELONG)”

Human sirtuins are seven proteins with deacetylase activity that are emerging as key modulators of basic physiological functions. Some evidence links SIRT3 to longevity in mammals. This study aimed to investigate whether variants within SIRT3 gene were associated to human longevity. We analyzed 549 genomic DNA collected during the prospective study “Treviso Longeva,” including elderly over 70 years of age from the municipality of Treviso, a small city in the northeast of Italy. We genotyped SIRT3 rs3825075, rs4980329, and rs11555236 single nucleotide polymorphisms (SNPs) by real-time polymerase chain reaction allelic discrimination assay. A cross-sectional analysis performed by comparing people over and under 85 years of age did not evidence association among the SIRT3 SNPs and longevity. However, when we performed a longitudinal analysis considering mortality as a dependent variable, we observed an association of SIRT3 rs11555236 and rs4980329 with longevity in the whole population (p values corrected for potential confounders = 0.04 and 0.03, respectively). After stratification according to gender, the same SNPs were associated to female longevity only (p values corrected for potential confounders = 0.03 and 0.02, respectively). Finally, as rs11555236 was reported to be in linkage disequilibrium with a putative functional enhancer within the SIRT3 gene, we assessed whether rs11555236 genotypes correlated with a different level of SIRT3 protein in peripheral blood mononuclear cells. We found an increased level of SIRT3 in subjects homozygous for the (T) allele. We suggest that SIRT3 genetic variability might be relevant for the modulation of human longevity in the Italian population.

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MAP3K7 and GSTZ1 are associated with human longevity: a two-stage case–control study using a multilocus genotyping

The pathways that regulate energy homeostasis, the mechanisms of damage repair, and the signaling response to internal environmental changes or external signals have been shown to be critical in modulating lifespan of model organisms and humans. In order to investigate whether genetic variation of genes involved in these pathways contribute to longevity, a two-stage case–control study in two independent sets of long-lived individuals from Calabria (Italy) was performed. In stage 1, 317 SNPs in 104 genes were analyzed in 78 cases (median age 98 years) and 71 controls (median age 67 years). In stage 2, 31 candidate SNPs identified in stage 1 (π_markers = 0.1) were analyzed in an independent sample composed by 288 cases (median age 92 years) and 554 controls (median age 67 years). Two SNPs, rs282070 located in intron 1 of the MAP3K7 gene, and rs2111699 located in intron 1 of the GSTZ1 gene, were significantly associated (after adjustment for multiple testing) with longevity in stage 2 (p = 1.1 × 10⁻³ and p = 1.4 × 10⁻³, respectively). Interestingly, both genes are implicated in the cellular response to internal and external environmental changes, playing a crucial role in the inflammation processes that accompany aging. Our data confirm that long-lived subjects are endowed with genetic variants that allow them to optimize these cellular responses and to better deal with environmental and internal stresses.

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Select aging biomarkers based on telomere length and chronological age to build a biological age equation

The purpose of this study is to build a biological age (BA) equation combining telomere length with chronological age (CA) and associated aging biomarkers. In total, 139 healthy volunteers were recruited from a Chinese Han cohort in Beijing. A genetic index, renal function indices, cardiovascular function indices, brain function indices, and oxidative stress and inflammation indices (C-reactive protein [CRP]) were measured and analyzed. A BA equation was proposed based on selected parameters, with terminal telomere restriction fragment (TRF) and CA as the two principal components. The selected aging markers included mitral annulus peak E anterior wall (MVEA), intima-media thickness (IMT), cystatin C (CYSC), D-dimer (DD), and digital symbol test (DST). The BA equation was: BA = −2.281TRF + 26.321CYSC + 0.025DD − 104.419MVEA + 34.863IMT − 0.265DST + 0.305CA + 26.346. To conclude, telomere length and CA as double benchmarks may be a new method to build a BA.     

Thigh muscle volume in relation to age, sex and femur volume

Secular changes and intra-individual differences in body shape and size can confound cross-sectional studies of muscle ageing. Normalising muscle mass to height squared is often suggested as a solution for this. We hypothesised that normalisation of muscle volume to femur volume may be a better way of determining the extent of muscle lost with ageing (sarcopenia). Thigh and femur muscle volumes were measured from serial magnetic resonance imaging sections in 20 recreationally active young men (mean age 22.4 years), 25 older men (72.3 years), 18 young women (22.1 years) and 28 older women (72.0 years). There were no age-related differences in femur volume. The relationship between thigh muscle volume and femur volume (R² = 0.76; exponent of 1.12; P < 0.01) was stronger than that with height (R² = 0.49; exponent of 3.86; P < 0.01) in young participants. For young subjects, the mean muscle/bone ratios were 16.0 and 14.6 for men and women, respectively. For older men and women, the mean ratios were 11.6 and 11.5, respectively. The Z score for the thigh muscle/bone volume ratio relative to young subjects was −2.2 ± 0.7 for older men and −1.4 ± 0.8 for older women. The extent of sarcopenia judged by the muscle/bone ratio was approximately twice that determined when normalising to height squared. These data suggest that the muscle/bone ratio captures the intra-individual loss of muscle mass during ageing, and that the age-related loss of muscle mass may be underestimated when normalised to height squared. The quadriceps seems relatively more affected by ageing than other thigh muscles.     

TTV DNA plasma load and its association with age,gender, and HCMV IgG serostatus in healthy adults

Understanding immunosenescence and changes in antimicrobial immune response with age is of high importance. The association of immunosenescence with gender and persistent infection with human cytomegalovirus (HCMV) is a matter of intensive research. We determined whether replication of another persistent and highly prevalent virus, Torque teno virus (TTV), is related to age, gender, and HCMV IgG serostatus of the host. TTV DNA load in plasma was assessed by real-time PCR in 313 healthy persons: 20–30 years old (young, n = 104), 50–60 years old (middle-aged, n = 101), or >80 years old (elderly, n = 108). TTV DNA loads were further associated with age-groups, gender, and HCMV IgG serostatus. TTV load was significantly higher in the elderly compared to the young group (p < 0.001; Tukey’s honest significant difference (HSD)), and the higher TTV DNA levels over age were found to be gender-specific (p = 0.002; ANOVA), with young women showing the lowest TTV load compared to young men (p = 0.009, t test) and compared to the other female age-groups (middle-aged p = 0.005; elderly p < 0.001; Tukey’s HSD). TTV load of HCMV IgG-seropositive persons was significantly higher than that of the HCMV IgG seronegative in the young (p = 0.005; t test) and middle-aged (p = 0.016; t test) groups. These results indicate that the host’s immune control of TTV replication decreases with age and is gender-specific. Persistent HCMV infection is significantly related to higher TTV DNA loads, especially at a younger age. Therefore, the influence of gender and HCMV on immunosenescence earlier in life should be further explored.     

Effects of acute bouts of endurance exercise on retinal vessel diameters are age and intensity dependent

Alterations of retinal vessel diameters are associated with increased cardiovascular risk. We aimed to investigate changes in retinal vessel diameters in response to acute dynamic exercise of different intensities and whether these changes are age dependent. Seventeen healthy seniors (median (IQR) age 68 (65, 69) years) and 15 healthy young adults (median (IQR) age 26 (25, 28) years) first performed a maximal treadmill test (MTT) followed by a submaximal treadmill test (SMTT) and a resting control condition in randomised order. Central retinal arteriolar (CRAE) and central retinal venular (CRVE) diameter equivalents were measured before as well as 5 (t₅) and 40 (t₄₀) minutes after exercise cessation using a static retinal vessel analyser. Both exercise intensities induced a significant dilatation in CRAE and CRVE at t₅ compared to the control condition (P < 0.001). At t₄₀, the mean increase in CRAE and CRVE was greater for MTT compared to that for SMTT (CRAE 1.7 μm (95 % confidence interval (CI) −0.1, 3.6; P = 0.061); CRVE 2.2 μm (95 % CI 0.4, 4.1; P = 0.019)). However, the estimated difference at t₅ between seniors and young adults in their response to MTT compared to SMTT was 5.3 μm (95 % CI 2.0, 8.5; P = 0.002) for CRAE and 4.1 μm (95 % CI −0.4, 8.6; P = 0.076) for CRVE. Wider arteries and veins after maximal versus submaximal exercise for seniors compared to young adults suggest that myogenic vasoconstriction in response to exhaustive exercise may be reduced in seniors. Age-related loss of vascular reactivity has clinical implications since the arteriolar vasoconstriction protects the retinal capillary bed from intraluminal pressure peaks.

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The uniqueness of subjective ageing: convergent and discriminant validity

Although a large body of research has demonstrated the predictive power of subjective ageing for several decisive developmental outcomes, there remains some controversy about whether subjective ageing truly represents a unique construct. Thus, information about the convergent and discriminant validity of different approaches to measuring subjective ageing is still critically needed. Using data from the 2014 wave of the German Ageing Survey, we examined how three established subjective ageing measures (subjective age, global attitude toward own ageing, multidimensional ageing-related cognitions) were inter-related as well as distinct from general dispositions (optimism, self-efficacy) and well-being (negative affect, depressive symptoms, self-rated health). Using correlational and multivariate regression analysis, we found that the three subjective ageing measures were significantly inter-related (r = |.09| to |.30|), and that each measure was distinct from general dispositions and well-being. The overlap with dispositional and well-being measures was lowest for subjective age and highest for global attitudes towards own ageing. The correlation between global attitudes towards own ageing and optimism was particularly striking. Despite the high convergent validity of the different dimensions of ageing cognitions, we nevertheless observed stronger associations between specific dimensions of ageing cognitions with negative affect and self-rated health. We conclude that researchers should be aware of the multidimensional nature of subjective ageing. Furthermore, subjective age appears to be a highly aggregated construct and future work is needed to clarify its correlates and reference points.Electronic supplementary materialThe online version of this article (10.1007/s10433-019-00529-7) contains supplementary material, which is available to authorized users.     

Effects of aging and sex on voluntary activation and peak relaxation rate of human elbow flexors studied with motor cortical stimulation

Data are equivocal on whether voluntary activation is preserved or decreased in old compared to young adults. Further, data are scant on the effect of age on the rate of muscle relaxation when the muscle is contracting voluntarily. Assessment of both measures with transcranial magnetic stimulation (TMS) yields information which cannot be obtained with traditional peripheral nerve stimulation. Hence, voluntary activation and peak relaxation rate of the elbow flexors were assessed with TMS during repeated maximal efforts in 30 men and 28 women between the ages of 22–84 years. Voluntary activation was similar for the two sexes (P = 0.154) and was not affected by age in men (96.2 ± 2.7 %; P = 0.887) or women (95.1 ± 3.0 %; P = 0.546). Men had a significantly faster peak rate of relaxation than women in absolute units (−880.0 ± 223.2 vs. −360.2 ± 78.5 Nm/ s, respectively; P < 0.001) and when normalized to subject strength (−12.5 ± 2.1 vs. −8.7 ± 1.0 s⁻¹, respectively; P < 0.001). Absolute and normalized relaxation rates slowed with age in men (P = 0.002 and P = 0.006, respectively), but not women (P = 0.142 and P = 0.950, respectively). Across the age range studied, all subjects, regardless of age or sex, were able to achieve high voluntary activation scores for the elbow flexors (~95 %). In contrast, peak relaxation rate was markedly faster in men than women and slowed with age in men but not women. Normalization of relaxation rates to strength did not affect the influence of age or sex.     

Genomics of human health and aging

Despite notable progress of the candidate-gene and genome-wide association studies (GWAS), understanding the role of genes contributing to human health and lifespan is still very limited. We use the Framingham Heart Study to elucidate if recognizing the role of evolution and systemic processes in an aging organism could advance such studies. We combine throughput methods of GWAS with more detail methods typical for candidate-gene analyses and show that both lifespan and ages at onset of CVD and cancer can be controlled by the same allelic variants. The risk allele carriers are at highly significant risk of premature death (e.g., RR = 2.9, p = 5.0 × 10⁻⁶⁶), onset of CVD (e.g., RR = 1.6, p = 4.6 × 10⁻¹⁷), and onset of cancer (e.g., RR = 1.6, p = 1.5 × 10⁻⁶). The mechanism mediating the revealed genetic associations is likely associated with biological aging. These aging-related phenotypes are associated with a complex network which includes, in this study, 62 correlated SNPs even so these SNPs can be on non-homologous chromosomes. A striking result is three-fold, highly significant (p = 3.6 × 10⁻¹⁰) enrichment of non-synonymous SNPs (N = 27) in this network compared to the entire qualified set of the studied SNPs. Functional significance of this network is strengthened by involvement of genes for these SNPs in fundamental biological processes related to aging (e.g., response to stimuli, protein degradation, apoptosis) and by connections of these genes with neurological (20 genes) and cardio-vascular (nine genes) processes and tumorigenesis (10 genes). These results document challenging role of gene networks in regulating human health and aging and call for broadening focus on genomics of such phenotypes.

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Chronic inhibition of the respiratory chain in human fibroblast cultures: differential responses related to subject chronological and biological age

Respiratory chain function becomes less efficient with age resulting in increased levels of damaging reactive oxygen species. We compared rotenone-exposed fibroblast strains from young and old subjects and from offspring of nonagenarian siblings and the partners of the offspring. Rotenone increased reactive oxygen species levels, inhibited growth rate, and increased telomere shortening (all p < .05). Non-stressed strains from young subjects showed lower reactive oxygen species levels (p = .031) and higher growth rates (p = .002) than strains from old subjects. Stressed strains from young subjects showed smaller increases in reactive oxygen species levels (p = .014) and larger decreases in growth rate (p < .001) than strains from old subjects. Telomere-shortening rates were not different between groups. Stress-induced decreases in growth rate were larger in strains from offspring than from partners (p = .05). Strains from young and old subjects are differentially affected by chronic inhibition of the respiratory chain. Changed growth rates in strains from offspring resemble those from strains from young subjects.     

Differential expression of elastic fibre components in intrinsically aged skin

Intrinsic ageing of the skin is a subtle process resulting in some degree of skin laxity. The dermal elastic fibre network imbues skin with the capacity to recoil and loss of this property contributes to an aged, wrinkled appearance. Whilst elastic fibres have a complex, composite structure which allows them to fulfil multiple roles, the effects of intrinsic ageing on their discrete molecular components has not previously been explored. In this study, we have used a microarray-based approach to perform a novel survey of the changes in gene expression that occur in components of cutaneous elastic fibres as a result of intrinsic ageing. Age-related changes in gene expression were validated at the mRNA and protein levels using quantitative real-time polymerase chain reaction (qPCR) and immunostaining, respectively. The microarray revealed that the majority of elastic fibre network components were unchanged with age. However, three differentially expressed genes were identified: latent TGFβ-binding protein (LTBP)-2 which was up-regulated with age (fold change +1.58, P = 0.041); LTBP3 (fold change −1.67, P = 0.025) and the lysyl oxidase-like enzyme (LOXL1, fold change −1.47, P = 0.008) which were both down-regulated with age. Although the changes in gene expression for LTBP3 were not confirmed by either qPCR or immunostaining, the expression and tissue deposition of both LTBP2 and LOXL1 were significantly enhanced in intrinsically aged skin. Whilst the functional implications of these altered expression profiles remains to be elucidated, LTBP2 and LOXL1 are thought to play important roles in controlling and maintaining elastic fibre deposition, assembly and structure via binding to fibulin-5. Consequently, any age-related perturbations in the expression of these components may have important consequences on remodelling of the extracellular matrix and hence on the mechanical properties of intrinsically aged skin.