Centenarian Offspring Research Articles

Investigating Alzheimer’s Disease Resistance in Okinawan Centenarians’ Offspring: A Population Study in a Blue Zone

Alzheimer’s disease (AD) is a neurodegenerative condition characterized by cognitive decline and the accumulation of amyloid-β plaques and neurofibrillary tangles in the brain. Although developing the disease becomes increasingly common as people age, centenarians — individuals who reach the age of 100 — have shown an unexpected resilience to AD, and these individuals are more prevalent in regions known as blue zones, where people experience exceptional longevity and health. This study focuses on the offspring of centenarians in one of these blue zones, Okinawa, Japan, to investigate what potential protective factors they may possess against AD. By screening this unique population using a questionnaire and the Mini-Mental State Examination (MMSE) and tracking AD pathology through advanced biomarker assays following the A/T/N criteria, A: Aβ40/42 ratio, T: phosphorylated tau (pT217-tau), and N: neurofilament light chain (NfL) levels, we aim to uncover genetic, environmental, or lifestyle-related factors that contribute to the decreased incidence of AD in these populations. This study seeks to identify key factors contributing to their resilience by comparing the results of centenarian offspring with age-matched non-centenarians. The spouses of these offspring of centenarians will also be included in the study, acting as a control group of individuals who are likely to share many of the lifestyle and environmental factors with the centenarian offspring but with different genetics. These findings could provide valuable insights for the future development of public health strategies and approaches to mitigate AD risk in the broader population.

MOSAIC CHROMOSOMAL ALTERATIONS AND LONGEVITY

Abstract Mosaic chromosomal alterations (mCAs) are structural alterations that are associated with mortality, age, cancer, cardiovascular disease, and diverse infections. The distribution of mCAs in long-lived subjects and individuals with familial longevity is not well described. We applied MOsaic CHromosomal Alteration (MoChA) caller on genome-wide genotype samples of 2025 centenarians, their siblings, and offspring and 273 unrelated controls from the New England Centenarian Study (NECS) and 3642 subjects with familial longevity and 920 controls from the Long-Life Family Study (LLFS). MoChA utilizes a Hidden Markov Model to detect mCA-induced deviations in allelic balance at heterozygous sites with Log R Ratio and B-allele frequency (BAF) with phased genotype information. We analyzed somatic mCAs in samples with genome-wide BAF phase concordance less than 0.51, LOD score greater than 10, and estimated cell fraction less than 50%. The results in the two studies showed that autosomal mCAs spanning over 100 kbase pairs increase with older age until approximately 102 years. However, the prevalence of the subjects with mCAs tends to plateau after that age, suggesting that the accumulation of mCAs is less prevalent in long-lived subjects. We also found that offspring and siblings of centenarians accumulate less autosomal mCAs (fixed-effect meta-analysis for NECS and LLFS: RR=0.78, p=0.033) compared to unrelated controls. In addition, consistent with results from other studies, mCAs are associated with increased risk for mortality (HR=1.08, p=0.02) and sex (Male RR=1.37, p=4.15e-05), and impact incident events of cancer, dementia, diabetes, and cardiovascular diseases even at extreme old ages.

Effects of Variability in Glycemic Indices on Longevity in Chinese Centenarians.

BackgroundLarge fluctuations in blood glucose levels greatly impact the health and life span of elderly individuals. This study describes the characteristics of variability in glycemic indices in centenarians with the aim of emphasizing the importance of glycemic variability in elderly people.MethodsWe recruited individuals from Rugao City, Jiangsu Province, China from April 2020 to May 2021. The study cohort included 60 centenarians and 60 first-generation offspring, as well as 20 randomly selected non-cohabitant control individuals aged 60–80 years. A FreeStyle Libre H (hospital version) continuous glucose monitoring (CGM) device (Abbott Ireland UK) was used to measure glycemic variability. The indices measured included the time in target glucose range (TIR), time below target glucose range (TBR), time above target glucose range (TAR), mean amplitude of glycemic excursions (MAGE), mean of daily differences (MODD), coefficient of variation (CV), standard deviation of blood glucose (SDBG), continuous overlapping net glycemic action (CONGA), glucose management indicator (GMI) and estimated glycated hemoglobin (eHbA1c). Logistic regression was used to analyze the association between glycemic variability and longevity.ResultsMean blood glucose (MBG), eHbA1c, GMI, mean fasting plasma glucose (M-FPG) and CONGA were lower in the centenarian group (p all < 0.05). PPGE-2 was higher in the control group than that measured in the centenarian and first-generation offspring groups (p < 0.05). There were no differences between the groups in MAGE, MODD, MAG, or TIR (p > 0.05). The risk of not achieving longevity increased with each one unit increase in MBG by 126% [2.26 (1.05–4.91)], eHbA1c by 67% [1.67 (1.03–2.72)], GMI by 568% [6.68 (1.11–40.30)], M-FPG by 365% [4.65 (1.57–13.75)], M-PPG1h by 98% [1.98 (1.18–3.31)], CONGA1 by 102% [2.02 (1.01–4.06)], Li by 200% [3.00 (1.04–8.61)], and PPGE-2 by 150% [2.50 (1.39–4.50)]. However, the risk of achieving longevity decreased with each unit increase of LBGI by 53% [0.47 (0.28–0.80)], ADRR by 60% [0.40 (0.18–0.86)], and TBR by 11% [0.89 (0.80–0.98)].ConclusionFluctuation in blood glucose levels in centenarians is relatively small. Maintaining an average blood glucose level and keeping blood glucose fluctuations in the normal range is conducive to longevity.

BMI, Blood Pressure, and Plasma Lipids among Centenarians and Their Offspring.

Background The burden of cardiovascular diseases (CVDs) is increasing substantially due to population growth and aging. Determining effective prevention and understanding the underlying mechanisms remain desirable pursuits for increasing the quality of life. As centenarians and their offspring may have genetic advantages, they may present with healthier cardiovascular-related profiles. Methods We launched a cross-sectional household-based survey of centenarian families, including 253 centenarians, 217 centenarian offspring, and 116 offspring spouses without centenarian parents from county-level Chinese longevity city Rugao. Among offspring and offspring spouses were the following arrangements: 101 paired offspring and offspring spouses who lived together, 116 unpaired offspring, and 16 unpaired spouses. We investigated their cardiovascular-related health status including waist circumference, body mass index (BMI), blood pressure, and plasma lipids and compared results among centenarians, centenarian offspring, and offspring spouses. Results Centenarians ranged from 99 to 109 years with a median age of 100 years. Centenarian offspring, with a median age of 70 years, and offspring spouses, with a median age of 69 years, shared similar age. Results of blood pressure, plasma lipid levels, and BMI displayed no significant difference between centenarian offspring and offspring spouses. However, centenarians appeared to have lower waist circumference, BMI, TC, LDL-C, TG, and diastolic blood pressure but higher levels of systolic blood pressure (p < 0.05). Multivariate analysis showed the prevalence of obesity, hypertension, and dyslipidemia was similar between centenarian offspring and offspring spouses, while centenarians appeared to have a lower prevalence of obesity and a higher prevalence of hypertension (p < 0.05). Conclusions Centenarians and centenarian offspring did not present healthier BMI, blood pressure, or plasma lipids than offspring spouses. Further research on longevity and cardiovascular diseases are desirable.

Thyroid hormones and frailty in persons experiencing extreme longevity.

The aging phenotype is quite heterogeneous, being the result of the capability of each individual to successfully or unsuccessfully response to stressors. The reduction of homeostatic reserve characterizing aging is accompanied by a remodeling of the endocrine system. Frailty has been indicated as a promising way for capturing the physiological decline as well as the biological aging of the individuals. In particular, the Frailty Index (FI), based on the assumption that health deficits tend to accumulate with aging, represents a quantitative measure of extreme interest. The study aims to correlate the thyroid hormone levels with FI in a population of centenarians and their offspring to capture the effects of thyroid remodeling in extreme longevity. The study described 593 well-characterized Italian subjects, including 180 centenarians, as well as 276 centenarian's offspring and 137 age-matched controls. FT3 levels and FT3/FT4 ratio were significantly lower (p<0.001) and TSH levels higher (p<0.001) in centenarians compared to the other groups, analysing both overall subjects and excluding subjects with hormone levels out of the normal ranges. In overall centenarians, we observed a negative correlation between FI and FT3 (ρ: -0.281, p<0.001), FT3/FT4 (ρ: -0.344, p<0.001) and TSH (ρ: -0.223, p 0.003) and a positive association between FI and FT4 (ρ: 0.189, p=0.001). In centenarians with hormone levels within the normal ranges, similar negative correlations were observed between FI and FT3 (ρ: -0.201, p=0.02) and FT3/FT4 (ρ: -0.264, p=0.002). In this sub-analysis, FI positively correlated with FT4 and age (ρ: 0.167, p=0.05; ρ: 0.219, p=0.005, respectively). Conversely, no significant correlations were observed between hormone levels and FI in offspring and controls. We found an association between thyroid hormone levels and frailty in centenarians, underlying the significant role of thyroid in the aging process and longevity.

Prevalence and Loads of Torquetenovirus in the European MARK-AGE Study Population.

Torquetenovirus (TTV) viremia has been associated with increased mortality risk in the elderly population. This work aims to investigate TTV viremia as a potential biomarker of immunosenescence. We compared levels of circulating TTV in 1813 participants of the MARK-AGE project, including human models of delayed (offspring of centenarians [GO]) and premature (Down syndrome [DS]) immunosenescence. The TTV load was positively associated with age, cytomegalovirus (CMV) antibody levels, and the Cu/Zn ratio and negatively associated with platelets, total cholesterol, and total IgM. TTV viremia was highest in DS and lowest in GO, with intermediate levels in the SGO (spouses of GO) and RASIG (Randomly Recruited Age-Stratified Individuals From The General Population) populations. In the RASIG population, TTV DNA loads showed a slight negative association with CD3+T-cells and CD4+T-cells. Finally, males with ≥4log TTV copies/mL had a higher risk of having a CD4/CD8 ratio<1 than those with lower viremia (odds ratio [OR] = 2.85, 95% confidence interval [CI]: 1.06-7.62), as well as reduced CD3+ and CD4+T-cells compared to males with lower replication rates (<4log), even after adjusting for CMV infection. In summary, differences in immune system preservation are reflected in the models of delayed and premature immunosenescence, displaying the best and worst control over TTV replication, respectively. In the general population, TTV loads were negatively associated with CD4+ cell counts, with an increased predisposition for an inverted CD4/CD8 ratio for individuals with TTV loads ≥4log copies/mL, thus promoting an immune risk phenotype.

A SERUM PROTEIN SIGNATURE OF APOE GENOTYPES IN CENTENARIANS

The discovery of treatments to prevent or delay Alzheimer’s disease is a priority. The gene APOE is associated with cognitive change and late onset Alzheimer’s disease, and epidemiological studies have shown that the e_2 allele of APOE has a neuroprotective effect, and it is associated with increased longevity. We correlated APOE genotype data of 222 New England Centenarian Study participants, including 79 centenarians, 84 centenarian offspring and 55 carriers of APOE e_2, with aptamer-based serum proteomics (SomaLogic technology) of 4783 human proteins corresponding to 4137 genes. We discovered a signature of 16 proteins that associated with different APOE genotypes, and replicated the signature in 3 independent studies. We show that the protein signature tracks with gene expression profiles in brains of late onset Alzheimer’s disease vs. healthy controls. Finally, we show that seven of these proteins correlate with cognitive function changes. Therefore, targeting APOE e_2 molecularly may preserve cognitive function.

A serum protein signature of APOE genotypes in centenarians.

The discovery of treatments to prevent or delay dementia and Alzheimer's disease is a priority. The gene APOE is associated with cognitive change and late‐onset Alzheimer's disease, and epidemiological studies have provided strong evidence that the e 2 allele of APOE has a neuroprotective effect, it is associated with increased longevity and an extended healthy lifespan in centenarians. In this study, we correlated APOE genotype data of 222 participants of the New England Centenarian Study, including 75 centenarians, 82 centenarian offspring, and 65 controls, comprising 55 carriers of APOE e 2, with aptamer‐based serum proteomics (SomaLogic technology) of 4,785 human proteins corresponding to 4,137 genes. We discovered a signature of 16 proteins that associated with different APOE genotypes and replicated the signature in three independent studies. We also show that the protein signature tracks with gene expression profiles in brains of late‐onset Alzheimer's disease versus healthy controls. Finally, we show that seven of these proteins correlate with cognitive function patterns in longitudinally collected data. This analysis in particular suggests that Baculoviral IAP repeat containing two (BIRC2) is a novel biomarker of neuroprotection that associates with the neuroprotective allele of APOE. Therefore, targeting APOE e 2 molecularly may preserve cognitive function.

Heterogeneity of Thyroid Function and Impact of Peripheral Thyroxine Deiodination in Centenarians and Semi-Supercentenarians: Association With Functional Status and Mortality.

Thyroid hormones (FT3, FT4) and thyroid-stimulating hormone (TSH) were evaluated in a population of 672 well-characterized Italian subjects (age range: 52-113 years), including an unprecedented number of centenarians, semi-supercentenarians, as well as centenarian's offspring and age-matched elderly (CENT, 105+, CENTOFF, and CTRL, respectively). The results show that FT3 level and FT3/FT4 ratio decrease while FT4 and TSH increase in an age-dependent manner. In CENT/105+, higher FT4 level, and lower FT3/FT4 ratio are associated with an impaired functional status and an increased mortality. A cluster analysis identified three clusters of CENT/105+ based on their FT3, FT4, and TSH levels. Cluster 3, characterized by lower FT3 and TSH and higher FT4, shows the worst health status and the shortest survival. Thus, the age-related changes of thyroid hormones extend to the most advanced age, and CENT/105+ are highly heterogeneous regarding thyroid function. This heterogeneity is related to different health, functional and cognitive status, as well as with survival/mortality in CENT/105+. Finally, we investigated a remarkable number of CENT/105+ showing a thyroid profile suggestive of non-thyroidal illness syndrome (NTIS) (excluded from the previous analysis). NTIS CENT/105+ are characterized by a worse functional and cognitive status and an increased mortality with respect to CENT/105+ without NTIS.

Reduced Prevalence and Incidence of Cognitive Impairment Among Centenarian Offspring.

Centenarian offspring have better health and lower mortality in comparison to referent cohorts, however it is unknown whether they have preserved cognition at older ages. This prospective study of 491 centenarian offspring and 270 referent participants without familial longevity (mean baseline age 75.5 years) from the New England Centenarian Study analyzed longitudinal cognitive assessments performed using the Telephone Interview for Cognitive Status. Logistic regression was used for cognitive impairment at baseline and Cox proportional hazards regression for risk of incident cognitive impairment. After adjustment for age, sex, education, stroke, and diabetes, offspring were 46% less likely to have baseline cognitive impairment (adjusted odds ratio 0.54, 95% CI 0.35-0.82) and were 27% less likely to become cognitively impaired over a median follow-up of 7.8 years (adjusted hazard ratio 0.73, 95% CI 0.53-0.99). Female gender was also independently associated with lower odds of baseline cognitive impairment and lower risk of incident cognitive impairment. Familial longevity may confer exposure to genetic and environmental factors that predispose centenarian offspring to preservation of cognitive function at older ages. Centenarian offspring cohorts may provide an opportunity to study cognitive resilience associated with familial longevity.

P-110 - Centenarian offspring: A model for understanding healthy aging

Centenarians exhibit extreme longevity showing a compression of morbidity. We showed previously that microRNA expression profiles and plasma protein carbonylation in centenarians and young people are similar, whereas they are very different from that found in old individuals. This suggests that centenarians have a better control of homeostasis and are protected against oxidative damage. In this study, we aimed to determine if such characteristic microRNA expression profile and lower protein oxidation status in centenarians may be inherited by their offspring. For this purpose, we collected plasma and peripheral blood mononuclear cells from 90 septuagenarians, 68 centenarians and 46 centenarian offspring. MicroRNA expression profile was performed using the Genechip miRNA 2.0 Array and protein carbonylation by OxyBlot TM Protein Oxidation Detection kit. Our results showed that microRNA expression pattern in centenarians is similar to centenarian offspring and different to septuagenarians. We observed a significant decrease in plasma protein carbonylation levels in centenarians and centenarian offspring when compared to septuagenarians. In conclusion, centenarian offspring resemble centenarian characteristics, and could be a model of healthy aging in humans.

Sicilian centenarian offspring are more resistant to immune ageing.

Immunosenescence constitutes a major indirect cause of morbidity and mortality in the elderly. Previous analysis of immune signatures in a cohort of centenarian offspring showed an intermediate immunophenotype between age-matched and younger controls. To confirm and extend the previous studies performing further phenotypical analysis in centenarian offspring and controls. Analysis of Treg cells, γδ T cells, mucosal-associated invariant T cells, and senescent immune T cells was performed in centenarian offspring and controls. We report significant differences between elderly and centenarian offspring in most of the studied subsets, showing that centenarian offspring subsets present an intermediate phenotyping between elderly and younger people. The whole present data confirm and extend the previous results showing that centenarian offspring retain more youthful immunological parameters and that the exhaustion of the immune system is less evident than in elderly without centenarian parents, though further investigations are warranted.

Purpose in Life Among Centenarian Offspring.

Purpose in life (PIL), a feeling of meaning and direction in life, is associated with favorable health outcomes including lower mortality and reduced risk of disease, disability, and cognitive impairment. Since centenarian offspring have been shown to have long health spans we sought to examine whether they have higher PIL than individuals without familial longevity. We compared PIL scores from the Ryff Scales of Psychological Well-Being in centenarian offspring from the New England Centenarian Study (N = 361, mean age = 82.0 years) with 3 referent groups: spouses, birth cohort-matched referents, and Health and Retirement Study (HRS) participants. Logistic regression analyses adjusted for age, sex, education, and marital status indicated greater odds of high PIL among centenarian offspring compared with spouse (adjusted odds ratio [aOR] = 1.92, 95% confidence interval [CI] = 1.002-3.68, p = .049) and birth cohort referents (aOR = 2.64, 95% CI = 1.36-5.14, p = .004). Offspring had an almost 3 times greater odds of having high PIL than HRS participants (odds ratio [OR] = 2.93, 95% CI = 2.17-3.96, p < .0001). Higher PIL is associated with being an offspring of a long-lived parent and may play a role in the ability to delay age-associated illnesses and functional decline. Increasing purposefulness may be a target for interventions to promote healthy aging.

Association between Sleep Patterns and Health in Families with Exceptional Longevity.

Sleep patterns such as longer sleep duration or napping are associated with poor health outcomes. Although centenarians and their offspring demonstrate a delayed onset of age-related diseases, it is not known whether they have healthier sleep patterns or are protected against the negative effects of sleep disturbances. Data on sleep patterns and health history were collected from Ashkenazi Jewish subjects of the Longevity Genes Project using standardized questionnaires. Participants included individuals with exceptional longevity (centenarians) with preserved cognition (n = 348, median age 97 years), their offspring (n = 513, median age 69 years), and controls (n = 199) age-matched to the offspring. Centenarians reported on their sleep patterns at age 70, while the offspring and controls on their current sleep patterns. Biochemical parameters were measured at baseline. Models were adjusted for age, sex, BMI, and use of sleep medication. The offspring and controls reported similar sleep patterns, with 33% sleeping ≥8 h and 17% napping in each group. At age 70, centenarians were more likely to have slept ≥8 h (55%) and to have napped (28%) compared with offspring and controls, p < 0.01. Among centenarians, no association was noted between sleep patterns and health outcomes. Sleeping for ≥8 h was associated with lower high-density lipoprotein cholesterol levels in the offspring and controls, and with insulin resistance in the offspring, but not with diabetes. Napping was associated with insulin resistance among the controls (p < 0.01), but not the offspring. Controls, but not offspring, who napped were 2.79 times more likely to have one or more of the following diseases: hypertension, myocardial infarction, stroke, or diabetes (OR 2.79, 95% CI 1.08-7.21, p = 0.04). Despite being more likely to exhibit risky sleep patterns at age 70 compared with the offspring and controls, the centenarians were protected from age-related morbidities. The offspring of centenarians did exhibit metabolic disturbances in association with less healthy sleep patterns; however, unlike the controls, they were much less likely to manifest age-related diseases. This suggests that offspring may have inherited resilience genotypes from their centenarian parents that protect them against the harmful effects of sleep disturbances.

Assortative Mating by Ethnicity in Longevous Families.

Recent work shows strong evidence of ancestry-based assortative mating in spouse pairs of the older generation of the Framingham Heart Study. Here, we extend this analysis to two studies of human longevity: the Long Life Family Study (LLFS), and the New England Centenarian Study (NECS). In the LLFS, we identified 890 spouse pairs spanning two generations, while in the NECS we used data from 102 spouse pairs including offspring of centenarians. We used principal components of genome-wide genotype data to demonstrate strong evidence of ancestry-based assortative mating in spouse pairs of the older generation and also confirm the decreasing trend of endogamy in more recent generations. These findings in studies of human longevity suggest that spouses marrying into longevous families may not be powerful controls for genetic association studies, and that there may be important ethnicity-specific, genetic influences and/or gene–environment interactions that influence extreme survival in old generations. In addition, the decreasing trend of genetic similarity of more recent generations might have ramifications for the incidence of homozygous rare variants necessary for survival to the most extreme ages.

Zinc-Induced Metallothionein in Centenarian Offspring From a Large European Population: The MARK-AGE Project.

Metallothionein (MT) family are cysteine-rich proteins that regulate zinc (Zn) homeostasis and protect against oxidative damage. Studies in transgenic mice have shown that MT favorably influence longevity, although their role in human aging is not completely understood. Within the European multicenter study MARK-AGE, we analyzed MT induction after Zn treatment in peripheral blood mononuclear cells (PBMCs) and its relation with redox biomarkers in 2,936 age-stratified subjects (35-75 years) including the general population (RASIG), centenarian offspring (GO), and their spouses (SGO). We found that the lymphocyte capability to induce MT in response to Zn is not affected by aging. However, GO participants showed lower Zn-induced MT and increased basal expression of MT1A, MT1X, and ZnT-1 genes than RASIG subjects. Moreover, Zn-induced MT levels were found to be inversely related with oxidative stress markers (plasma protein carbonyls, 3-nitrotyrosine, and malondialdehyde) in the whole population, but not in GO subjects. In conclusion, our results support the hypothesis that the response to Zn is attenuated in PBMCs of centenarian offspring compared to the general population as a consequence of a tighter control of Zn homeostasis which is likely to provide them constant protection against stress stimuli over the whole lifespan.

Centenarians' offspring as a model of healthy aging: a reappraisal of the data on Italian subjects and a comprehensive overview.

Within the scenario of an increasing life expectancy worldwide it is mandatory to identify determinants of healthy aging. Centenarian offspring (CO) is one of the most informative model to identify trajectories of healthy aging and their determinants (genetic and environmental), being representative of elderly in their 70th whose lifestyle can be still modified to attain a better health. This study is the first comprehensive investigation of the health status of 267 CO (mean age: 70.2 years) and adopts the innovative approach of comparing CO with 107 age-matched offspring of non-long-lived parents (hereafter indicated as NCO controls), recruited according to strict inclusion demographic criteria of Italian population. We adopted a multidimensional approach which integrates functional and cognitive assessment together with epidemiological and clinical data, including pro- and anti-inflammatory cytokines and adipokines, lipid profile, and insulin resistance. CO have a lower prevalence of stroke, cerebral thrombosis-hemorrhage, hypertension, hypercholesterolemia, and other minor diseases, lower BMI and waist circumference, a better functional and cognitive status and lower plasma level of FT4 compared to NCO controls. We conclude that a multidimensional approach is a reliable strategy to identify the health status of elderly at an age when interventions to modify their health trajectory are feasible.

Cellular Senescence and Inflammatory Burden as Determinants of Mortality in Elderly People Until the Extreme old age

Human aging is accompanied by a chronic low-grade inflammation, called “inflammaging”, a phenomenon associated with frailty, morbidity, and mortality in elderly people (Franceschi and Campisi, 2014). This condition is related to the accumulation of senescent cells in aged tissues through the senescence-associated secretory phenotype (SASP), which includes pro-inflammatory cytokines among its key constituents (Franceschi and Campisi, 2014). A well-known trigger of cellular senescence, closely related to inflammaging, is telomere length shortening. However, while considerable evidence shows that circulating inflammatory markers are predictors of mortality in community-living elderly individuals (Giovannini et al., 2011, Varadhan et al., 2014), there are conflicting results on the role of telomere length (Deelen et al., 2014, Bendix et al., 2014). Arai et al. (2015) in this issue of EbioMedicine demonstrate with a cross-sectional approach that telomere length, measured in the DNA extracted from whole blood of centenarian offspring, centenarians and (semi-)supercentenarians displays a superior maintenance compared to the one measured in community-living elderly subjects. Indeed, telomere length of centenarian offspring is maintained for more than 20 years at a length corresponding to 60 years of age in the general population. Interestingly, the authors observed that while long telomeres might be a prerequisite for exceptional lifespan in humans, they did not predict mortality. Conversely, Arai et al. confirmed that a multibiomarker score of systemic inflammation, which included anti-cytomegalovirus IgG, IL-6, TNF-α and C-reactive protein levels, was associated with an increased risk of mortality, loss of cognitive function and physical function decline, in normal aging and at extreme old age (up to 110 years). These data demonstrate that a multiple biomarker index may represent a more powerful predictor of mortality in older adults than a single inflammatory mediator, as also recently shown through a combined measure of interleukin 6 (IL-6) and soluble TNF receptor 1 (sTNFR1) (Varadhan et al., 2014). Therefore, the development of reliable measures of inflammatory status is of great interest in clinical practice both as risk assessment tools of age-related chronic diseases, and to monitor clinical progression or as a powerful surrogate biomarker in the research of new anti-inflammatory therapeutics. Hence, given that inflammation is a consolidated predictor of mortality, it is also important to investigate the sources of this phenomenon and their relative contribution. While it is known that cell senescence and inflammation can drive each other thus causing accelerated aging, the results of Arai and co-workers suggest that blood telomere length might not reflect the phenomenon of accumulation of senescent cells in various tissues and organs. This could be particularly true if accumulating senescent cells will be confirmed as a major source of circulating inflammatory markers in aging. The finding regarding the clearance of p16Ink4a-positive senescent cells which delay aging-associated disorders in genetically engineered mice (Baker et al., 2011) opens interesting future perspectives regarding therapeutic approaches aimed at the removal of senescent cells to prevent or delay tissue dysfunction and extend healthspan. However, senescent cells may also exert a physiological role as demonstrated for wound healing (Demaria et al., 2014) and their clearance could have adverse outcomes, especially in young organisms. For these reasons it is necessary to intensify the research effort in order to clarify the effects of the selective elimination of senescent damaged cells in aged animal models. In this context, the development of strategies to remove senescent cells could represent an emerging tool for the suppression of chronic inflammation and to ameliorate human healthy lifespan. A feasible and suggestive approach may be the employment of senolytic compounds (Zhu et al., 2015), in particular natural bioactive compounds, such as quercetin, which might be easily used in clinical trials, while minimizing the risk of adverse events (Malavolta et al., 2015).

Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians

To determine the most important drivers of successful ageing at extreme old age, we combined community-based prospective cohorts: Tokyo Oldest Old Survey on Total Health (TOOTH), Tokyo Centenarians Study (TCS) and Japanese Semi-Supercentenarians Study (JSS) comprising 1554 individuals including 684 centenarians and (semi-)supercentenarians, 167 pairs of centenarian offspring and spouses, and 536 community-living very old (85 to 99years). We combined z scores from multiple biomarkers to describe haematopoiesis, inflammation, lipid and glucose metabolism, liver function, renal function, and cellular senescence domains. In Cox proportional hazard models, inflammation predicted all-cause mortality with hazard ratios (95% CI) 1.89 (1.21 to 2.95) and 1.36 (1.05 to 1.78) in the very old and (semi-)supercentenarians, respectively. In linear forward stepwise models, inflammation predicted capability (10.8% variance explained) and cognition (8.6% variance explained) in (semi-)supercentenarians better than chronologic age or gender. The inflammation score was also lower in centenarian offspring compared to age-matched controls with Δ (95% CI)=−0.795 (−1.436 to −0.154). Centenarians and their offspring were able to maintain long telomeres, but telomere length was not a predictor of successful ageing in centenarians and semi-supercentenarians. We conclude that inflammation is an important malleable driver of ageing up to extreme old age in humans.

Double negative (CD19+IgG+IgD−CD27−) B lymphocytes: A new insight from telomerase in healthy elderly, in centenarian offspring and in Alzheimer's disease patients

Immunosenescence is characterized by the impairment of humoral immunity with changes in the memory/naive B cell compartment. In particular we have previously reported the percentage increase of a Memory IgD−CD27− (Double Negative, DN) B cell population in aged people. In this study, we have further characterized DN B cells with the aim to better understand their contribution to immunosenescence. As DN B cells show a poor ability to proliferate in vitro, we have evaluated the expression of the inhibitory receptors CD307d and CD22 on these cells from young and old individuals. In addition we have evaluated the ability to activate DN B cells by the simultaneous use of innate (CpG) and adaptive (α-Ig/CD40) ligands. Our data demonstrate that the refractoriness to proliferate of DN B cells does not depend on the expression of inhibitory receptors, but it is due to the kind of stimulation. Indeed, when DN B cells are stimulated engaging both BCR and TLR9, they become able to proliferate and reactivate the telomerase enzyme. In the present study, we have also compared the telomerase activity in a group of people genetically advantaged for longevity as centenarian offspring (CO) and in a group of moderate–severe Alzheimer's disease (AD) patients, who represent a model of unsuccessful aging. Our study suggests that telomerase reactivation of DN B cells, as well as their number and ability in activating, depend essentially by the biological age of the subjects studied, so the evaluation of DN B cells might allow to gain insight to healthy and unsuccessful aging.