Rejuvenation in distinct cell populations – What does it mean?

Rejuvenation represents a well organized and tightly regulated cellular process in vitro and in vivo, whereby senescent and/or certain differentiated cells revert specific properties acquired during previous steps of maturation to restore again a younger phenotype. Effects of the microenvironment and cellular mechanisms including asymmetric mitosis or retrodifferentiation can contribute to rejuvenation during a dynamic cellular development in contrast to terminally differentiated cells like unicellular organisms, which appear unable to retrodifferentiate and to rejuvenate. The process of rejuvenation is observed in distinct cell populations and includes a coordinated multistep network of transduction cascades with extracellular signaling and cell-to-cell communication to relay intracellular pathways. This provides a certain tissue homeostasis by a regenerative potential and renewal upon tissue-specific repair requirements in addition to residual stem cells, which can vary among different organs and species to extend their life span. However, dysfunctions within a rejuvenation program may also include the risk of neoplastic growth during such a retrograde development. In contrast to rejuvenation in certain cell types, a life span extension – also termed longevity – does not represent a retrograde development but an overall prolonged function of tissues, organs and/or whole organisms. Thus, rejuvenation of a distinct cell population could contribute to longevity of the corresponding organism but may not necessarily be required since longevity could also be achieved mechanistically by inhibition of the mTOR-mediated signaling pathway or by sufficient supply of anti-oxidative defence compounds, physiologically by nutrient restrictions, genetically by the induction of longevity genes or environmentally by the inhibition of aging.     

Complement factor H 402His variant confers an increased mortality risk in Finnish nonagenarians: The Vitality 90+ study

Ageing is characterized by chronic low-grade inflammation and the expected lifespan may be affected by several immunological and inflammatory mediators. In this study, we investigated whether the functional Tyr402His polymorphism (rs1061170) on complement factor H (CFH) gene, which is a key inflammatory downregulator, modulates the longevity of 491 nonagenarians in the Vitality 90+ study. Logistic regression analysis and Kaplan–Meier method with the log rank test were used to examine the effect of the CFH Tyr402His polymorphism on 4-year mortality. After follow-up, we observed that risk factor-adjusted mortality was significantly higher among the carriers of CFH 402His allele compared to non-carriers (OR 1.78, 95% CI 1.19–2.67, p = 0.005) and that the survival curves of CFH 402His carriers and non-carriers deviated significantly (p = 0.016). We propose that the increased mortality is inflammation-related and mediated by aberrant complement regulation by the CFH 402His variant.     

Bionomics of Aedes aegypti subpopulations (Diptera: Culicidae) from Misiones Province, northeastern Argentina

Life statistics of four Aedes aegypti subpopulations from the subtropical province of Misiones were studied during autumn and winter, under semi-natural conditions, coming from the localities of Posadas (SW), San Javier (SE), Bernardo de Irigoyen (NE) and Puerto Libertad (NW). The eastern subpopulations are geographically separated by the central mountain system of the province from the western subpopulations. High percentages of larval and pupal survival (97-100%) were recorded, and no significant differences were detected among the four subpopulations. Larvae and pupae lasted approximately 8 days to complete their development, no significant differences being detected among the four subpopulations studied. Sex ratio recorded did not differ significantly from 1:1. Male longevity did not show difference among the different subpopulations, but female longevity was remarkably different among the four subpopulations (F = 16.27; d.f. = (3;8); P = 0.0009), ranging among 11.45 days for San Javier and 57.87 days for Posadas. Fecundity also varied considerably among subpopulations, the greatest number (307.44 eggs/female) being recorded for Posadas (F = 4.13; d.f. = (3;8); P = 0.04). Ae. aegypti females of the western subpopulations lived longer than the eastern subpopulations studied, therefore, the risk of dengue outbreak would be greater on the Misiones Province border with Paraguay.     

Mitochondrial J haplogroup is associated with lower blood pressure and anti-oxidant status: findings in octo/nonagenarians from the BELFAST Study

Mitochondria produce cellular energy but also free-radicals, which damage cells despite an array of endogenous anti-oxidants. In Northern Europe, the mitochondrial haplogroup J has been related to longevity in nonagenarians and centenarians but also with age-related disease. Hypertension is an important contributor to atherosclerotic-related diseases and its pathogenesis is associated with increased oxidative stress. In this study, we questioned whether J haplogroup octo/nonagenarians from the Belfast Elderly Longitudinal Free-living Elderly STudy (BELFAST) study showed evidence of protective blood pressure or anti-oxidant profile which might explain their longevity advantage. Briefly, in a cross-sectional study, community-living, mentally alert (Folstein >25/30), octo/nonagenarian subjects, recruited for good health, were enlisted and consented as part of the BELFAST study, for blood pressure, anthropometric measurements and blood sampling. DNA typing for mitochondrial haplotypes was carried out with measurements for enzymatic and non-enzymatic antioxidants. J haplogroup carriers showed lower systolic blood pressure and glutathione peroxidase activity (Gpx) with higher folate measurements. There was no change in urate, bilirubin, albumin or nutrition-related antioxidants-selenium or vitamins A, C and α and β carotene. BELFAST study mtDNA J haplogroup octo/nonagenarians showed lower blood pressure and reduced glutathione peroxidase activity and higher folate, but no change for other antioxidants. These findings are of interest in view of mtDNA J haplogroup’s association with increased age in some previous studies.     

Gene set analysis of GWAS data for human longevity highlights the relevance of the insulin/IGF-1 signaling and telomere maintenance pathways

In genome-wide association studies (GWAS) of complex traits, single SNP analysis is still the most applied approach. However, the identified SNPs have small effects and provide limited biological insight. A more appropriate approach to interpret GWAS data of complex traits is to analyze the combined effect of a SNP set grouped per pathway or gene region. We used this approach to study the joint effect on human longevity of genetic variation in two candidate pathways, the insulin/insulin-like growth factor (IGF-1) signaling (IIS) pathway and the telomere maintenance (TM) pathway. For the analyses, we used genotyped GWAS data of 403 unrelated nonagenarians from long-lived sibships collected in the Leiden Longevity Study and 1,670 younger population controls. We analyzed 1,021 SNPs in 68 IIS pathway genes and 88 SNPs in 13 TM pathway genes using four self-contained pathway tests (PLINK set-based test, Global test, GRASS and SNP ratio test). Although we observed small differences between the results of the different pathway tests, they showed consistent significant association of the IIS and TM pathway SNP sets with longevity. Analysis of gene SNP sets from these pathways indicates that the association of the IIS pathway is scattered over several genes (AKT1, AKT3, FOXO4, IGF2, INS, PIK3CA, SGK, SGK2, and YWHAG), while the association of the TM pathway seems to be mainly determined by one gene (POT1). In conclusion, this study shows that genetic variation in genes involved in the IIS and TM pathways is associated with human longevity.     

Role of VEGF gene variability in longevity: a lesson from the Italian population

Vascular endothelial growth factor (VEGF) gene polymorphisms have been associated with an increased risk of developing a wide variety of disorders from diabetes to neurodegenerative diseases suggesting functions not confined to its vascular effects originally described. Based on the VEGF protective roles undisclosed in pathological conditions, we evaluate whether VEGF variability might be a determinant also for longevity. Four polymorphisms (−2578C/A, −1190G/A, −1154G/A and −634G/C) within the VEGF gene promoter region in 490 unrelated Italian healthy subjects have been analysed. Significant changes of allele, genotype (−2578/AA versus −2578/CC: OR = 2.08, p = 0.007; −1190/AA versus −1190/GG: OR = 2.01, p = 0.011) and haplotype (AAGG: 10.4% versus 14.9%, p = 0.03) frequency distributions were observed between young/elderly (25–84 years old) and long-lived (85–99 years old) subjects. These results suggest that VEGF gene variability can be inserted among the genetic factors influencing the lifespan.     

Exercise and longevity

Aging is a natural and complex physiological process influenced by many factors, some of which are modifiable. As the number of older individuals continues to increase, it is important to develop interventions that can be easily implemented and contribute to “successful aging”. In addition to a healthy diet and psychosocial well-being, the benefits of regular exercise on mortality, and the prevention and control of chronic disease affecting both life expectancy and quality of life are well established. We summarize the benefits of regular exercise on longevity, present the current knowledge regarding potential mechanisms, and outline the main recommendations. Exercise can partially reverse the effects of the aging process on physiological functions and preserve functional reserve in the elderly. Numerous studies have shown that maintaining a minimum quantity and quality of exercise decreases the risk of death, prevents the development of certain cancers, lowers the risk of osteoporosis and increases longevity. Training programs should include exercises aimed at improving cardiorespiratory fitness and muscle function, as well as flexibility and balance. Though the benefits of physical activity appear to be directly linked to the notion of training volume and intensity, further research is required in the elderly, in order to develop more precise recommendations, bearing in mind that the main aim is to foster long-term adherence to physical activity in this growing population.     

C-reactive protein and glucose regulation in familial longevity

Earlier, we showed that the offspring from exceptionally long-lived families have a more favorable glucose metabolism when compared with controls. As chronic low-grade inflammation has been regarded as a strong risk factor for insulin resistance, we evaluated if and to what extent the favorable glucose metabolism in offspring from long-lived families could be explained by differences in subclinical inflammation, as estimated from circulating levels of C-reactive protein. We found no difference between the two groups in C-reactive protein levels or in the distribution of C-reactive protein haplotypes. However, among controls higher levels of C-reactive protein were related to higher glucose levels, whereas among offspring levels of C-reactive protein were unrelated to glucose levels. It is a limitation of the current study that its cross-sectional nature does not allow for assessment of cause–effect relationships. One possible interpretation of these data is that the offspring from long-lived families might be able to regulate glucose levels more tightly under conditions of low-grade inflammation. To test this hypothesis, our future research will be focused on assessing the robustness of insulin sensitivity in response to various challenges in offspring from long-lived families and controls.     

Increased lifespan in hyposulfatemic NaS1 null mice

Sulfate (SO₄²⁻) plays an important role in mammalian growth and development. In this study, hyposulfatemic NaS1 null (Nas1−/−) mice were used to investigate the consequences of perturbed SO₄²⁻ homeostasis on longevity. Median life spans were increased (by ≈ 25%) in male and female Nas1−/− mice when compared with Nas1+/+ mice. At 1 yr of age, serum SO₄²⁻ levels remained low in Nas1−/− mice (≈ 0.16 mM) when compared to Nas1+/+ mice (≈ 0.96 mM). RT-PCR revealed increased hepatic mRNA levels of Sirt1 (by ≈60%), Cat (by ≈48%), Hdac3 (by ≈22%), Trp53 and Cd55 (by ≈36%) in Nas1−/− mice, genes linked to ageing. Histological analyses of livers from 2 yr old mice revealed neoplasms in > 50% of Nas1+/+ mice but not in Nas1−/− mice. This is the first study to report increased lifespan, decreased hepatic tumours and increased hepatic expression of genes linked to ageing in hyposulfatemic Nas1−/− mice, implicating a potential role of SO₄²⁻ in mammalian longevity and cancer.