Strong and weak lifespan extension: What is most feasible and likely?

Recent advances in biomedical science indicate that it may eventually be possible to intervene in the biological process of human ageing. This paper overviews the current state of the science of lifespan extension and promising future directions. It is uncertain whether 'strong' lifespan extension - the extension of human life beyond the maximum 122 years so far observed - will become a reality. It is more likely that cumulative effects of numerous scientific and biomedical advances in the treatment of common disease will produce 'weak' lifespan extension - the extension of average life expectancy. The practical application of molecular, genetic and nanomaterials research may also lead to advances in life expectancy. It is not too early to begin to consider the policy implications of either form of lifespan extension.

The bridging of pluralistic visions of science and ethics for bioethics - Tibetan medicine as compared with the Western research on longevity and human genetic enhancement

La thèse examine les liens entre la vision pluraliste de la science et l’éthique de la médecine tibétaine et les nouvelles pratiques en médecine occidentale, soit la longévité et la recherche sur la génétique amélioratrice. Elle cherche à cerner l’apport que la médecine tibétaine peut apporter aux recherches occidentales sur la longévité et la génétique humaine amélioratrice. Elle traite donc d’un enjeu social clé et du débat qui s’y rattache. La découverte et la description sont centrales à la méthodologie et informent l’analyse. Nous avons examiné dans un premier temps, les travaux de recherche sur la longévité reliée à la génétique amélioratrice (mémoire et muscles). Nous nous sommes penchés également sur les fondements de la médecine tibétaine en tant que système intégré. Pour ce faire, nous avons traité des notions telles que la santé, l’identité, la perfection et l’immortalité. Notre cadre conceptuel repose sur la théorie bouddhiste de l’interdépendance qui se caractérise par la formulation de catégories qui ensuite sont synthétisées dans l’essence; les deux niveaux d’interprétation de la théorie sont décrits en détail avant de passer à une comparaison avec la notion de complexité occidentale. La médecine tibétaine de fait présente un système où l’éthique et la science sont intégrées et se prête bien à une comparaison avec la vision pluraliste de la science à partir d’une perspective éthique/bioéthique. Les commentaires recueillis auprès des experts nous ont permis de cerner comment la science, l’éthique et l’amélioration de la longévité sont définies au sein des deux paradigmes de l’Est et de l’Ouest. Nos résultats montrent six points qui se dégagent au terme de cette recherche permettent de jeter un pont sur la vision pluraliste de ces paradigmes. Ceux-ci transcendent les points de vue doctrinaux individuels de religions ainsi que du monde scientifique occidental. Plus que tout, ils laissent entrevoir un cadre de références novatrices qui contribuera à la prise de décision à l’égard de questionnements bioéthiques.

Modelling the dynamics of Plasmodium falciparum histidine-rich protein 2 in human malaria to better understand malaria rapid diagnostic test performance

BACKGROUND: Effective diagnosis of malaria is a major component of case management. Rapid diagnostic tests (RDTs) based on Plasmodium falciparumhistidine-rich protein 2 (PfHRP2) are popular for diagnosis of this most virulent malaria infection. However, concerns have been raised about the longevity of the PfHRP2 antigenaemia following curative treatment in endemic regions. METHODS: A model of PfHRP2 production and decay was developed to mimic the kinetics of PfHRP2 antigenaemia during infections. Data from two human infection studies was used to fit the model, and to investigate PfHRP2 kinetics. Four malaria RDTs were assessed in the laboratory to determine the minimum detectable concentration of PfHRP2. RESULTS: Fitting of the PfHRP2 dynamics model indicated that in malaria naive hosts, P. falciparum parasites of the 3D7 strain produce 1.4 x 10(-)(1)(3) g of PfHRP2 per parasite per replication cycle. The four RDTs had minimum detection thresholds between 6.9 and 27.8 ng/mL. Combining these detection thresholds with the kinetics of PfHRP2, it is predicted that as few as 8 parasites/muL may be required to maintain a positive RDT in a chronic infection. CONCLUSIONS: The results of the model indicate that good quality PfHRP2-based RDTs should be able to detect parasites on the first day of symptoms, and that the persistence of the antigen will cause the tests to remain positive for at least seven days after treatment. The duration of a positive test result following curative treatment is dependent on the duration and density of parasitaemia prior to treatment and the presence and affinity of anti-PfHRP2 antibodies.

Comparative analysis of genome maintenance genes in naked mole rat, mouse, and human

Genome maintenance (GM) is an essential defense system against aging and cancer, as both are characterized by increased genome instability. Here, we compared the copy number variation and mutation rate of 518 GM-associated genes in the naked mole rat (NMR), mouse, and human genomes. GM genes appeared to be strongly conserved, with copy number variation in only four genes. Interestingly, we found NMR to have a higher copy number of CEBPG, a regulator of DNA repair, and TINF2, a protector of telomere integrity. NMR, as well as human, was also found to have a lower rate of germline nucleotide substitution than the mouse. Together, the data suggest that the long-lived NMR, as well as human, has more robust GM than mouse and identifies new targets for the analysis of the exceptional longevity of the NMR.

Mitochondrial DNA 5178A polymorphism and longevity

Previous studies have shown that mitochondrial DNA (mtDNA) 5178 adenine/cytosine (5178A) polymorphism, which is one of the haplogroup-specific mutations for mtDNA haplogroup D, was apparently associated with aging and longevity in humans. We genotyped the

Absence of association between SNPs in the promoter region of the insulin-like growth factor 1 (IGF-1) gene and longevity in the Han Chinese population

Previous studies have indicated that genetic variations in the factors of insulin/insulin-like growth factor 1 (IGF-1) signaling pathway could influence human life-span by affecting IGF-1 levels. The promoter region of the IGF-1 gene is an obvious candida

Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study

BACKGROUND: Family studies and heritability estimates provide evidence for a genetic contribution to variation in the human life span. METHODS:We conducted a genome wide association study (Affymetrix 100K SNP GeneChip) for longevity-related traits in a community-based sample. We report on 5 longevity and aging traits in up to 1345 Framingham Study participants from 330 families. Multivariable-adjusted residuals were computed using appropriate models (Cox proportional hazards, logistic, or linear regression) and the residuals from these models were used to test for association with qualifying SNPs (70, 987 autosomal SNPs with genotypic call rate [greater than or equal to]80%, minor allele frequency [greater than or equal to]10%, Hardy-Weinberg test p [greater than or equal to] 0.001).RESULTS:In family-based association test (FBAT) models, 8 SNPs in two regions approximately 500 kb apart on chromosome 1 (physical positions 73,091,610 and 73, 527,652) were associated with age at death (p-value < 10-5). The two sets of SNPs were in high linkage disequilibrium (minimum r2 = 0.58). The top 30 SNPs for generalized estimating equation (GEE) tests of association with age at death included rs10507486 (p = 0.0001) and rs4943794 (p = 0.0002), SNPs intronic to FOXO1A, a gene implicated in lifespan extension in animal models. FBAT models identified 7 SNPs and GEE models identified 9 SNPs associated with both age at death and morbidity-free survival at age 65 including rs2374983 near PON1. In the analysis of selected candidate genes, SNP associations (FBAT or GEE p-value < 0.01) were identified for age at death in or near the following genes: FOXO1A, GAPDH, KL, LEPR, PON1, PSEN1, SOD2, and WRN. Top ranked SNP associations in the GEE model for age at natural menopause included rs6910534 (p = 0.00003) near FOXO3a and rs3751591 (p = 0.00006) in CYP19A1. Results of all longevity phenotype-genotype associations for all autosomal SNPs are web posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007. CONCLUSION: Longevity and aging traits are associated with SNPs on the Affymetrix 100K GeneChip. None of the associations achieved genome-wide significance. These data generate hypotheses and serve as a resource for replication as more genes and biologic pathways are proposed as contributing to longevity and healthy aging.

Trade-offs between cancer and other diseases: do they exist and influence longevity?

Relationships between aging, disease risks, and longevity are not yet well understood. For example, joint increases in cancer risk and total survival observed in many human populations and some experimental aging studies may be linked to a trade-off between cancer and aging as well as to the trade-off(s) between cancer and other diseases, and their relative impact is not clear. While the former trade-off (between cancer and aging) received broad attention in aging research, the latter one lacks respective studies, although its understanding is important for developing optimal strategies of increasing both longevity and healthy life span. In this paper, we explore the possibility of trade-offs between risks of cancer and selected major disorders. First, we review current literature suggesting that the trade-offs between cancer and other diseases may exist and be linked to the differential intensity of apoptosis. Then we select relevant disorders for the analysis (acute coronary heart disease [ACHD], stroke, asthma, and Alzheimer disease [AD]) and calculate the risk of cancer among individuals with each of these disorders, and vice versa, using the Framingham Study (5209 individuals) and the National Long Term Care Survey (NLTCS) (38,214 individuals) data. We found a reduction in cancer risk among old (80+) men with stroke and in risk of ACHD among men (50+) with cancer in the Framingham Study. We also found an increase in ACHD and stroke among individuals with cancer, and a reduction in cancer risk among women with AD in the NLTCS. The manifestation of trade-offs between risks of cancer and other diseases thus depended on sex, age, and study population. We discuss factors modulating the potential trade-offs between major disorders in populations, e.g., disease treatments. Further study is needed to clarify possible impact of such trade-offs on longevity.

Assessing the sensitivity of blue mussel beds to pressures associated with human activities.

The Joint Nature Conservation Committee (JNCC) commissioned this project to generate an improved understanding of the sensitivities of blue mussel (Mytilus edulis) beds, found in UK waters, to pressures associated with human activities in the marine environment. The work will provide an evidence base that will facilitate and support management advice for Marine Protected Areas, development of UK marine monitoring and assessment, and conservation advice to offshore marine industries. Blue mussel beds are identified as a Habitat of Principle Importance (HPI) under the Natural Environment and Rural Communities (NERC) Act 2006, as a Priority Marine Feature (PMF) under the Marine (Scotland) Act 2010, and included on the OSPAR (Annex V) list of threatened and declining species and habitats. The purpose of this project was to produce sensitivity assessments for the blue mussel biotopes included within the HPI, PMF and OSPAR habitat definitions, and clearly document the supporting evidence behind the assessments and any differences between them. A total of 20 pressures falling in five categories - biological, hydrological, physical damage, physical loss, and pollution and other chemical changes - were assessed in this report. The review examined seven blue mussel bed biotopes found on littoral sediment and sublittoral rock and sediment. The assessments were based on the sensitivity of M. edulis rather than associated species, as M. edulis was considered the most important characteristic species in blue mussel beds. To develop each sensitivity assessment, the resistance and resilience of the key elements are assessed against the pressure benchmark using the available evidence gathered in this review. The benchmarks were designed to provide a ‘standard’ level of pressure against which to assess sensitivity. Blue mussel beds were highly sensitive to a few human activities: • introduction or spread of non-indigenous species (NIS); • habitat structure changes - removal of substratum (extraction); and • physical loss (to land or freshwater habitat). Physical loss of habitat and removal of substratum are particularly damaging pressures, while the sensitivity of blue mussel beds to non-indigenous species depended on the species assessed. Crepidula fornicata and Crassostrea gigas both had the potential to outcompete and replace mussel beds, so resulted in a high sensitivity assessment. Mytilus spp. populations are considered to have a strong ability to recover from environmental disturbance. A good annual recruitment may allow a bed to recovery rapidly, though this cannot always be expected due to the sporadic nature of M. edulis recruitment. Therefore, blue mussel beds were considered to have a 'Medium' resilience (recovery within 2-10 years). As a result, even where the removal or loss of proportion of a mussel bed was expected due to a pressure, a sensitivity of 'Medium' was reported. Hence, most of the sensitivities reported were 'Medium'. It was noted, however, that the recovery rates of blue mussel beds were reported to be anywhere between two years to several decades. In addition, M. edulis is considered very tolerant of a range of physical and chemical conditions. As a result, blue mussel beds were considered to be 'Not sensitive' to changes in temperature, salinity, de-oxygenation, nutrient and organic enrichment, and substratum type, at the benchmark level of pressure. The report found that no distinct differences in overall sensitivity exist between the HPI, PMF and OSPAR definitions. Individual biotopes do however have different sensitivities to pressures, and the OSPAR definition only includes blue mussel beds on sediment. These differences were determined by the position of the habitat on the shore and the sediment type. For example, the infralittoral rock biotope (A3.361) was unlikely to be exposed to pressures that affect sediments. However in the case of increased water flow, mixed sediment biotopes were considered more stable and ‘Not sensitive’ (at the benchmark level) while the remaining biotopes were likely to be affected.

Using a clearly documented, evidence-based approach to create sensitivity assessments allows the assessment basis and any subsequent decision making or management plans to be readily communicated, transparent and justifiable. The assessments can be replicated and updated where new evidence becomes available ensuring the longevity of the sensitivity assessment tool. For every pressure where sensitivity was previously assessed as a range of scores in MB0102, the assessments made by the evidence review have supported one of the MB0102 assessments. The evidence review has reduced the uncertainty around assessments previously undertaken in the MB0102 project (Tillin et al., 2010) by assigning a single sensitivity score to the pressures as opposed to a range. Finally, as blue mussel bed habitats also contribute to ecosystem function and the delivery of ecosystem services, understanding the sensitivity of these biotopes may also support assessment and management in regard to these. Whatever objective measures are applied to data to assess sensitivity, the final sensitivity assessment is indicative. The evidence, the benchmarks, the confidence in the assessments and the limitations of the process, require a sense-check by experienced marine ecologists before the outcome is used in management decisions.

Is the phenotypic combination A1B8Cw7DR3 a marker for male longevity?

To study whether individual Human Leucocyte Antigens (HLA) at the HLA 1 or 11 loci or the phenotypic combination A1B8Cw7DR3 were associated with longevity.

Comparative biology of mammalian telomeres: hypotheses on ancestral states and the roles of telomeres in longevity determination

Progressive telomere shortening from cell division (replicative aging) provides a barrier for human tumor progression. This program is not conserved in laboratory mice, which have longer telomeres and constitutive telomerase. Wild species that do ⁄ do not use replicative aging have been reported, but the evolution of different phenotypes and a conceptual framework for understanding their uses of telomeres is lacking. We examined telomeres ⁄ telomerase in cultured cells from > 60 mammalian species to place different uses of telomeres in a broad mammalian context. Phylogeny-based statistical analysis reconstructed ancestral states. Our analysis suggested that the ancestral mammalian phenotype included short telomeres (< 20 kb, as we now see in humans) and repressed telomerase. We argue that the repressed telomerase was a response to a higher mutation load brought on by the evolution of homeothermy. With telomerase repressed, we then see the evolution of replicative aging. Telomere length inversely correlated with lifespan, while telomerase expression co-evolved with body size. Multiple independent times smaller, shorter-lived species changed to having longer telomeres and expressing telomerase. Trade-offs involving reducing the energetic ⁄ cellular costs of specific oxidative protection mechanisms (needed to protect < 20 kb telomeres in the absence oftelomerase) could explain this abandonment of replicative aging. These observations provide a conceptual framework for understanding different uses of telomeres in mammals, support a role for human-like telomeres in allowing longer lifespans to evolve, demonstrate the need to include telomere length in the analysis of comparative studies of oxidative protection in the biology of aging, and identify which mammals can be used as appropriate model organisms for the study of the role of telomeres in human cancer and aging. Key words: evolution of telomeres; immortalization; telomerase; replicative aging; senescence.

Microbes central to human reproduction

As studies uncover the breadth of microbes associated with human life, opportunities will emerge to manipulate and augment their functions in ways that improve health and longevity. From involvement in the complexities of reproduction and fetal/infant development, to delaying the onset of disease, and indeed countering many maladies, microbes offer hope for human well-being. Evidence is emerging to suggest that microbes may play a beneficial role in body sites traditionally viewed as being sterile. Although further evidence is required, we propose that much of medical dogma is about to change significantly through recognition and understanding of these hitherto unrecognized microbe–host interactions. A meeting of the International Scientific Association for Probiotics and Prebiotics held in Aberdeen, Scotland (June 2014), presented new views and challenged established concepts on the role of microbes in reproduction and health of the mother and infant. This article summarizes some of the main aspects of these discussions.

Immune Responses and Therapeutic Antitumor Effects of an Experimental DNA Vaccine Encoding Human Papillomavirus Type 16 Oncoproteins Genetically Fused to Herpesvirus Glycoprotein D

Recombinant adenovirus or DNA vaccines encoding herpes simplex virus type 1 (HSV-1) glycoprotein D (gD) genetically fused to human papillomavirus type 16 (HPV-16) oncoproteins (E5, E6, and E7) induce antigen-specific CD8(+) T-cell responses and confer preventive resistance to transplantable murine tumor cells (TC-1 cells). In the present report, we characterized some previously uncovered aspects concerning the induction of CD8(+) T-cell responses and the therapeutic anticancer effects achieved in C57BL/6 mice immunized with pgD-E7E6E5 previously challenged with TC-1 cells. Concerning the characterization of the immune responses elicited in mice vaccinated with pgD-E7E6E5, we determined the effect of the CD4(+) T-cell requirement, longevity, and dose-dependent activation on the E7-specific CD8(+) T-cell responses. In addition, we determined the priming/boosting properties of pgD-E7E6E5 when used in combination with a recombinant serotype 68 adenovirus (AdC68) vector encoding the same chimeric antigen. Mice challenged with TC-1 cells and then immunized with three doses of pgD-E7E6E5 elicited CD8(+) T-cell responses, measured by intracellular gamma interferon (IFN-gamma) and CD107a accumulation, to the three HPV-16 oncoproteins and displayed in vivo antigen-specific cytolytic activity, as demonstrated with carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled target cells pulsed with oligopeptides corresponding to the H-2D(b)-restricted immunodominant epitopes of the E7, E6, or E5 oncoprotein. Up to 70% of the mice challenged with 5 x 10(5) TC-1 cells and immunized with pgD-E7E6E5 controlled tumor development even after 3 days of tumor cell challenge. In addition, coadministration of pgD-E7E6E5 with DNA vectors encoding pGM-CSF or interleukin-12 (IL-12) enhanced the therapeutic antitumor effects for all mice challenged with TC-1 cells. In conclusion, the present results expand our previous knowledge on the immune modulation properties of the pgD-E7E6E5 vector and demonstrate, for the first time, the strong antitumor effects of the DNA vaccine, raising promising perspectives regarding the development of immunotherapeutic reagents for the control of HPV-16-associated tumors.

The costs of education, longevity and the poverty of nations

This paper explores the distortions on the cost of education, associated with government policies and institutional factors, as an additional determinant of cross-country income differences. Agents are finitely lived and the model takes into account life-cycle features of human capital accumulation. There are two sectors, one producing goods and the other providing educational services. The model is calibrated and simulated for 89 economies. We find that human capital taxation has a relevant impact on incomes, which is amplified by its indirect effect on returns to physical capital. Life expectancy plays an important role in determining long-run output: the expansion of the population working life increases the present value of the flow of wages, which induces further human capital investment and raises incomes. Although in our simulations the largest gains are observed when productivity is equated across countries, changes in longevity and in the incentives to educational investment are too relevant to ignore.