Long-lived honey bees (Apis mellifera) develop in fall. This pattern may be explained by reduced nurse loads. When the amount of brood in colonies declines as a function of adverse foraging conditions, adult bees build up surplus nutrient stores that include vitellogenin, a behavioral affector protein that also can increase lifespan. Although the seasonal reduction in exposure to nursing tasks predictably results in vitellogenin accumulation, the assumption that long-lived adults thereby develop is confounded by a concomitant decline in foraging effort. Foraging activity reduces lifespan, and is influenced by colony resource consumption, brood pheromones, availability of nectar and pollen, and weather. Here, we perform the first controlled experiment where the nursing environment of pre-foraging sister bees was set to vary, while their foraging environment later was set to be the same. We measure vitellogenin, age at foraging onset and lifespan. We establish that reduced brood-rearing increases vitellogenin levels, and delays foraging onset and death. Longevity is largely explained by the effect of nursing on the onset of foraging behavior, but is also influenced by the level of brood-rearing independent of behavioral change. Our findings are consistent with the roles of vitellogenin in regulation of honey bee behavior and lifespan.
Much of life history theory analyzes life histories of independent, isolated individuals, who grow, forage, reproduce, and die. However, in many species social interactions such as food sharing are a key part of the life history strategy, altering the energetic budget constraint. Transfers and sharing raise reproductive success and also alter the fitness impact of other aspects of the life history. We discuss a variety of traits and behaviors for which transfers are important, synthesizing results from a number of earlier papers. Topics include the U-shaped mortality curve, post reproductive survival, causes of early life mortality decline, why intergenerational transfers evolve and co-evolve with longevity, time preference, sexual dimorphism and sexual differences in transfers, menopause, demographic advantages of social sharing, and consequences of social sharing for life history evolution.
transfers; intergenerational; menopause; mortality; sexual dimorphism; life history
Individuals in a large experimental field population, of the short-lived perennial species Plantago lanceolata, were followed to determine the sources of variation that influence mortality and life span. The design included multiple age groups with initially similar genetic structure, which made it possible to separate age effects from period effects and to identify the genetic component to variation in life span. During a period of stress, individuals of all ages showed parallel increases in mortality but different cohorts experienced this period of high mortality at different ages. This then influenced the distribution of life spans across cohorts. Age and size-age interactions influenced mortality during the period of stress. Smaller individuals died but only if they were old. Additionally, growth and age interacted with stress such that older individuals had negative growth and high mortality whereas younger individuals had positive growth and relatively lower mortality during stress. The results of this study show that it is not simply the environment that can have a major impact on demography in natural populations, rather, age, size and growth can interact with the environment to influence mortality and life span when the environment is stressful.
Demography; natural population; life history; condition-dependent aging; plant senescence
Humans are the longest living and slowest growing of all primates. Although most primates are social, humans are highly cooperative and social in ways that likely co-evolved with the slow human life history. In this paper we highlight the role of resource transfers and non-material assistance within and across generations in shaping low human mortality rates. The use of complex cooperative strategies to minimize risk is a necessary precursor for selecting further reductions in mortality rate in late adulthood. In conjunction with changes in the age-profile of production, the impacts of resource transfers and other forms of cooperation on reducing mortality likely played an important role in selection on post-reproductive lifespan throughout human evolution. Using medical data and ethnographic interviews, we explore several types of common risks experienced by Tsimane forager-horticulturalists, and quantify the types and targets of aid. Our results illustrate the importance of transfers in several key domains and suggest that the absence of transfers would greatly increase human mortality rates throughout the life course.
intergenerational transfers; sharing; life history evolution; longevity; Tsimane
Evolutionary theories of aging suggest that trade-offs between longevity and fitness should be found under certain conditions. In C. elegans, there is little evidence for the existence of such tradeoffs. We asked if fertility/longevity trade-offs exist in populations of randomly mating males and hermaphrodites. We set up a large population of young males and 5-day-old hermaphrodites that were no longer self-fertile. We then allowed them to mate for one day with an equal number young males and then separated hermaphrodites to individual plates and determined daily fertility of individual hermaphrodites. There was a significant negative relationship between late-life fertility and individual longevity.
Genetics; Nematodes; Fertility; Demography; Longevity; Evolutionary Theory; Antagonistic Pleiotropy
Interest in stage-and age structured models has recently increased because they can describe quantitative traits such as size that are left out of age-only demography. Available methods for the analysis of effects of vital rates on lifespan in stage-structured models have not been widely applied because they are hard to use and interpret, and tools for age and stage structured populations are missing. We present easily interpretable expressions for the sensitivities and elasticities of life expectancy to vital rates in age-stage models, and illustrate their application with two biological examples. Much of our approach relies on trading of time and mortality risk in one stage for time and risk in others. Our approach contributes to the new framework of the study of age- and stage-structured biodemography.
Mulit-state models; age-stage structure; survival; markov chain process; life history evolution; perturbation analysis
The purpose of this study is to examine the relative importance of the force-based and velocity-based measures of muscle performance to explain inter-individual differences in power production capability and functional task performance. Participants included seventy-nine men and women: middle-aged healthy adults (MH: 40–55 years), older healthy adults (OH: 70–85 years), and older adults with mobility limitations (OML: 70–85 years). Muscle power at 180°/s, isometric maximal torque, and maximal contraction velocity at 40% 1RM were measured during unilateral leg extension. The Short Physical Performance Battery (SPPB) was used to differentiate between healthy and mobility limited older adults. Functional task performance was assessed using multiple chair rise and stair climb tests. Leg extensor force (torque), but not maximal contraction velocity, was significantly associated with muscle power in MH. Both torque and velocity were significantly associated with muscle power in OH. Maximal velocity, but not torque, was associated with power in OML. Maximal velocity demonstrated an association with multiple chair rise time and stair climb time in OML, but not MH or OH. It is concluded that movement velocity is an increasingly important determinant of maximal power output with advancing age. Furthermore, movement velocity is also a critical component of functional task performance with aging and may contribute to functional deficits. These findings help to explain why the rate-dependent variable power has emerged as a critical component of both assessment and rehabilitation of muscular performance and physical function in older adults.
Power; Velocity; Strength; Aging; Function
While the mechanisms of cellular aging remain controversial, a leading hypothesis is that mitochondrial oxidative stress and mitochondrial dysfunction play a critical role in this process. Here, we provide data in aging rhesus macaques supporting the hypothesis that increased oxidative stress is a major characteristic of aging and may be responsible for the age-associated increase in mitochondrial dysfunction. We measured mitochondrial DNA (mtDNA) damage by quantitative PCR in liver and peripheral blood mononuclear cells of young, middle age, and old monkeys and show that older monkeys have increases in the number of mtDNA lesions. There was a direct correlation between the amount of mtDNA lesions and age, supporting the role of mtDNA damage in the process of aging. Liver from older monkeys showed significant increases in lipid peroxidation, protein carbonylations and reduced antioxidant enzyme activity. Similarly, peripheral blood mononuclear cells from the middle age group showed increased levels in carbonylated proteins, indicative of high levels of oxidative stress. Together, these results suggest that the aging process is associated with defective mitochondria, where increased production of reactive oxygen species results in extensive damage at the mtDNA and protein levels. This study provides valuable data based on the rhesus macaque model further validating age-related mitochondrial functional decline with increasing age and suggesting that mtDNA damage might be a good biomarker of aging.
mitochondrial DNA; aging; mitochondria; antioxidant enzymes; rhesus monkey; liver
The capacity of pre-habilitative conditioning – exercise performed a priori – to mitigate neuromuscular maladaptations to disuse is unclear. This study evaluated pre-habilitation by examining neuromuscular junctions (NMJs) and the myofibers they innervate in young adult and aged muscles. Within each age category, 40 rats were divided into four treatment groups: 1) Control, 2) hindlimb suspended (unloaded), 3) prehabilitative conditioning preceding hindlimb suspension, and 4) pre-habilitative conditioning alone. Cytofluorsecent staining was used to visualize NMJs, and histochemical staining to assess myofiber profiles (size and type). Statistical analysis featured 2-way ANOVA with main effects for age and treatment, along with interaction. NMJs consistently revealed significant (P ≤ 0.05) main effects for age, but not treatment, or interaction. Typically, aged NMJs showed elongated nerve terminal branching, and more dispersed post-synaptic clusters of ACh receptors, resulting in reduced post-synaptic area per given length of pre-synaptic branching. Analysis of myofiber profiles showed significant main effects for age, treatment, and their interaction. Aged myofibers were smaller than young ones and a higher percentage of them were Type I. Aged fibers experienced significantly greater unloading-induced atrophy than young ones. Pre-habilitative conditioning significantly attenuated unloading-induced atrophy among aged, but not young myofibers. It was also observed that pre-habilitative conditioning alone increased myofiber size among aged, but not young adult muscles. In summary, myofibers were more sensitive than NMJs to the treatment interventions implemented. Although more sensitive to the negative effects of muscle unloading, aged myofibers were also more responsive to the hypertrophic effects of pre-habilitative conditioning.
myofiber; synapse; atrophy; disuse; old; unweighting
Age-related changes in cancer mortality risk are important for understanding the processes of disease and aging interaction. The extent to which these age changes differ by sex further contributes to this understanding but has not been well studied to date. We conducted a systematic examination of dynamics and heterogeneity of age changes in cancer mortality rates for the top 14 cancer sites using vital statistics from the NCHS and SEER between 1969 and 2007. We assessed patterns of age changes in site-specific mortality rates in terms of both increase (age slope) and acceleration (change in age slope) as measured by the log-log acceleration rate (LLA). We assessed sex differences in mortality rates through sex mortality rate ratios and sex differences in age changes through comparisons of the LLA by sex. The logged male-to-female mortality ratios are positive but vary substantially with age in magnitude. And the age patterns of sex ratios also vary across sites. The LLA values show similar declines and hence slowdowns of mortality increment into or during old age for both sexes for most sites and periods. Post-reproductive changes in sex differences in cancer mortality are not entirely consistent with the estrogenic hypothesis about the anticarcinogenic effects of sex hormones and suggest the utility of the multistage model of disease progression for some tumor sites. Analysis of age dynamics and sex differences in cancer mortality may modify extant aging-related theories of carcinogenesis and frame future searches for specific explanatory factors.
aging; sex differences; cancer mortality; multistage progression; estrogen
Oxidative stress remains one of the most well studied, albeit somewhat contentious, causes of aging-related changes in humans. Consequently, a large number of putative antioxidant compounds are freely available in myriad formulations that are often not tested for their efficacy or regulated for quality control. Following the development of a Drosophila model of oxidative-stress dependent aging (p38 MAP Kinase (p38K) mutants) in our laboratory, we attempted to test the protective effect of some of these commonly available formulations against oxidative stress, stress induced motor defects and reduced life span in the p38K model. As environmental exposure to oxidizing toxins has been linked to a variety of human diseases, we also tested the efficacy of these supplements on chemically-induced models of oxidative stress (Paraquat and Hydrogen Peroxide exposure). Our results suggest that when added as a dietary supplement, some of these over-the-counter compounds, notably containing Açai extracts, confer significant protection for both the p38K-dependent genetic model as well as the toxin-induced model. These products were also remarkably effective at dampening stress-induced expression of the detoxifying enzyme GSTD1 and eliminating Paraquat induced circadian rhythm deficits. Overall, our results suggest potential benefits of dietary supplementation with some of these compounds, especially under conditions of elevated oxidative stress. These findings should be assessed in the context of other studies that seek to identify active principles in these extracts, determine their effective dosage for human consumption and evaluate the safety of long-term prophylactic applications.
Antioxidants; p38MAPK; Açai; oxidative stress; Paraquat
Cardiovascular dysfunction is a primary independent predictor of age-related morbidity and mortality. Frailty is associated with activation of inflammatory pathways and fatigue that commonly presents and progresses with age. Interleukin 10 (IL-10), the cytokine synthesis inhibitory factor, is an anti-inflammatory cytokine produced by immune and non-immune cells. Homozygous deletion of IL-10 in mice yields a phenotype that is consistent with human frailty, including age-related increases in serum inflammatory mediators, muscular weakness, higher levels of IGF-1 at midlife, and early mortality. While emerging evidence suggests a role for IL-10 in vascular protection, a clear mechanism has not yet been elucidated.
In order to evaluate the role of IL-10 in maintenance of vascular function, force tension myography was utilized to access ex-vivo endothelium dependent vasorelaxation in vessels isolated from IL-10 knockout IL-10(tm/tm) and control mice. Pulse wave velocity ((PWV), index of stiffness) of vasculature was measured using ultrasound and blood pressure was measured using the tail cuff method. Echocardiography was used to elucidated structure and functional changes in the heart.
Mean arterial pressures were significantly higher in IL-10(tm/tm) mice as compared to C57BL6/wild type (WT) controls. PWV was increased in IL-10(tm/tm) indicating stiffer vasculature. Endothelial intact aortic rings isolated from IL-10(tm/tm) mice demonstrated impaired vasodilation at low acetylcholine doses and vasoconstriction at higher doses whereas vasorelaxation responses were preserved in rings from WT mice. Cyclo-oxygenase (COX-2)/thromboxane A2 inhibitors improved endothelial dependent vasorelaxation and reversed vasoconstriction. Left ventricular end systolic diameter, left ventricular mass, isovolumic relaxation time, fractional shortening and ejection fraction were all significantly different in the aged IL-10(tm/tm) mice compared to WT mice.
Aged IL-10(tm/tm) mice have stiffer vessels and decreased vascular relaxation due to an increase in eicosanoids, specifically COX-2 activity and resultant thromboxane A2 receptor activation. Our results also suggest that aging IL-10(tm/tm) mice have an increased heart size and impaired cardiac function compared to age-matched WT mice. While further studies will be necessary to determine if this age-related phenotype develops as a result of inflammatory pathway activation or lack of IL-10, it is essential for maintaining the vascular compliance and endothelial function during the aging process. Given that a similar cardiovascular phenotype is present in frail, older adults, these findings further support the utility of the IL-10(tm/tm) mouse as a model of frailty.
Interleukin 10; Cyclo-oxygenase; Thromboxane; Endothelial dysfunction; Acetylcholine; Aorta; Frailty; Aging; Prostanoid; Cytokines
We tested the hypothesis that sodium nitrite treatment reverses large elastic artery stiffening in old mice via reductions in collagen I, increases in elastin and/or decreases in advanced glycation endproducts (AGEs) mediated by reduced oxidative stress. Aortic pulse wave velocity (aPWV), a measure of large elastic artery stiffness, was greater in old (26–28 mo) compared with young (4–6 mo) control animals (520 ± 9 vs. 405 ± 6 cm/s, p<0.05), and this was reversed by 3 weeks of sodium nitrite treatment (50 mg/L) (435 ± 17 cm/s). Age-related increases (p<0.05) in aortic superoxide production were associated with greater total and adventitial nitrotyrosine staining, all of which were reversed by nitrite treatment. Total and adventitial transforming growth factor β and collagen I were increased, and total and medial elastin were reduced with aging (p<0.05), but were unaffected by sodium nitrite. Aorta from old mice had increased total, adventitial and medial AGEs (p<0.05 vs. young), which were normalized by sodium nitrite treatment. In aortic segments from young mice in vitro, pyrogallol (10 µM), a superoxide generator, induced an “aging-like” increase in AGEs, and direct treatment with AGEs induced vascular stiffening; these effects were prevented by incubation with sodium nitrite. De-stiffening of aged large elastic arteries by short-term sodium nitrite therapy is mediated in part by normalization of AGEs secondary to amelioration of oxidative stress.
arterial stiffness; collagen; elastin; nitrotyrosine; superoxide
In contrast to many other complex traits, the natural genetic architecture of life expectancy has not been intensely studied, particularly in non-model organisms, such as the honey bee (Apis mellifera L.). Multiple factors that determine honey bee worker lifespan have been identified and genetic analyses have been performed on some of those traits. Several of the traits are included in a suite of correlated traits that form the pollen hoarding syndrome, which was named after the behavior to store surplus pollen in the nest and is tied to social evolution. Here, seven quantitative trait loci that had previously been identified for their effects on different aspects of the pollen hoarding syndrome were studied for their genetic influence on the survival of adult honey bee workers. To gain a more comprehensive understanding of the genetic architecture of worker longevity, a panel of 280 additional SNP markers distributed across the genome was also tested. Allelic distributions were compared between young and old bees in two backcross populations of the bi-directionally selected high- and low-pollen hoarding strain. Our results suggest a pleiotropic effect of at least one of the behavioral quantitative trait loci on worker longevity and one significant and several other putative genetic effects in other genomic regions. At least one locus showed evidence for strong antagonistic pleiotropy and several others suggested genetic factors that influence pre-emergence survival of worker honey bees. Thus, the predicted association between worker lifespan and the pollen hoarding syndrome was supported at the genetic level and the magnitude of the identified effects also strengthened the view that naturally segregating genetic variation can have major effects on age-specific survival probability in the wild.
Longevity; Lifespan; Social Evolution; Division of Labor; QTL; Pleiotropy; Genetic Architecture
Non-human primates (NHP) represent an emerging animal model for the study of physical function, and provide opportunities for exploration of relationships of muscle biomolecular changes with age. One such primate model, the African green vervet monkey, has been used extensively in biomedical research but little is known regarding skeletal muscle composition, expression of myosin heavy chain (MHC) isoforms, and changes with age. In the present study we examined the effects of age on vastus lateralis (VL) muscle fiber-type composition, fiber cross-sectional area (CSA), and MHC isoforms expressed in 4 young and 4 older adult vervet monkeys. Proteomics analysis, using a human and nonhuman primate protein database, showed five MHC isoforms (I, IIA, IIX, IIB, and IIB′) expressed in female vervet VL muscle, which matched the human MHC isoforms. Fast type II fibers predominated and no pure type IIB or IIB′ containing fibers were detected. Hybrid fibers containing IIB/IIB′ MHC decreased in the old vervets. The CSA of both type I and type II fibers was significantly smaller in older vervet while type IIA fibers showed the most severity of atrophy. The decrease of fast MHC and atrophy of muscle fiber with aging recapitulate observations in human VL muscle. These findings, along with its homology of MHC between the vervet and human suggested that the vervet monkey may be a suitable preclinical model for understanding the cellular and molecular basis of sarcopenia and for developing new interventions to ameliorate the impact of disorders that affect skeletal muscle structure and function.
myosin heavy chain; aging; non-human primate; vervet
Macronutrient balance is a critical contributor in modulating lifespan and health. Consumption of diets rich in fruits and vegetables provides numerous health benefits. The interactions among macronutrients and botanicals and how they influence aging and health remain elusive. Here we employed a nutritional geometry approach to investigate the interplay among dietary fat, sugar, protein and antioxidant- and polyphenolic-rich freeze-dried açai pulp in modulating lifespan and reproductive output in the Mexican fruit fly, Anastrepha ludens (Loew). Individual flies were cultured on one of the 24 diets made from a combination of 1) sugar and yeast extract (SY) at four ratios, 2) palmitic acid, a saturated fat, at two concentrations and 3) freeze-dried açai pulp at three concentrations. Fat addition decreased lifespan in females on the sugar only diet and the diet with a low SY ratio, while decreasing lifetime reproductive output in flies on the diet with the low SY ratio when compared to SY ratio-matched low fat controls. Açai supplementation promoted survival, while decreasing lifetime reproductive output, in flies on diets with high fat and high sugar but not other diets when compared to diet-matched non-supplemented controls. These findings reveal that the impact of fat and açai on lifespan and reproductive output depends on the dietary content of other macronutrients. Our results reveal the intricate interplay among macronutrients and nutraceuticals, and underscore the importance of taking macronutrient balance into consideration in designing dietary interventions for aging and health.
Palmitic acid; Lifespan; Dietary intervention; Nutraceutical; Palm fruit; Anastrepha ludens
Dry eye disease is a prevalent eye disorder that in particular affects the elderly population. One of the major causes of dry eye, meibomian gland dysfunction (MGD), shows increased prevalence with aging. MGD is caused by hyperkeratinization of the ductal epithelium of meibomian gland and reduced quantity and/or quality of meibum, the holocrine product that stabilizes and prevents the evaporation of the tear film. Of note, retinoids which are used in current anti-aging cosmetics may promote the development of MGD and dry eye disease. In this review, we will discuss the possible mechanisms of age-related MGD.
aging; meibomian gland dysfunction (MGD); dry eye disease; FOXO; retinoic acid; androgens; stem cell; growth hormone; insulin-like growth factor-1 (IGF-1); insulin sensitivity
Alveolar macrophages (AMs) are the first immune cells to respond to an invading pathogen and coordinate the inflammatory response within the lungs. Studies suggest that macrophages exhibit age-related deficiencies in Toll-like receptor (TLR) function; however, the impact of this dysfunction during pneumonia, the leading cause of infectious death in the elderly, and the underlying mechanisms responsible remain unclear. We examined disease severity in young, mature, and aged BALB/cBy mice following intratracheal infection with the Gram-positive bacteria Streptococcus pneumoniae (Spn). Both mature and aged mice failed to clear bacteria and as a result had increased mortality, tissue damage and vascular leakage. Early production of TNFα, IL-1β, and IL-6 during pneumonia declined with age and was associated with an inability of isolated AMs to respond to pneumococcal cell wall (CW) and ethanol-killed Spn ex vivo. Total levels of TLR1 were unaffected by age and TLR2 surface expression was slightly yet significantly increased on aged AMs suggesting that intracellular TLR signaling defects were responsible for the age-related decline in cytokine responsiveness. Following infection of isolated AMs with live Spn, a significant age-related decline in TLR2-induced phosphorylation of p65 NFκB, JNK and p38 MAPK, and an increase in ERK phosphorylation was observed by immunoblotting. These data are the first to demonstrate that TLR2-dependent recognition of Spn by aged AMs is impaired and is associated with a delayed pro-inflammatory cytokine response in vivo along with enhanced susceptibility to pneumococcal pneumonia.
Aging; pneumonia; macrophages; alveolar macrophages; Streptococcus pneumoniae; Toll-like receptor; Cell signaling; Tumor necrosis factor α; Interleukin-6; MAPK; p65; p38; JNK; ERK
Changes of factors circulating in the systemic environment during human aging have been investigated for a long time. Only recently however, miRNAs have been found to be secreted into the systemic and tissue environments where they are protected from RNAses by either carrier proteins or by being packaged into microvesicles. These miRNAs are then taken up by recipient cells, changing the cellular behavior by the classical miRNA induced silencing of target mRNAs. The origin of circulating miRNAs, however, is in most instances unclear, but senescent cells emerge as a possible source of such secreted miRNAs. Since differences in the circulating miRNAs have been found in a variety of age-associated diseases, and accumulation of senescent cells in the elderly emerges as a possible detrimental factor in aging, it is well conceivable that these miRNAs might contribute to the functional decline observed during aging of organisms.
Therefore, we here give an overview on current knowledge on microvesicular secretion of miRNAs, changes of the systemic and tissue environments during aging of cells and organisms. Finally, we summarize current knowledge on miRNAs that are found to be specific for age-associated diseases.
► miRNAs are secreted within microvesicles. ► Little is known about miRNA secretion in cellular and organismal aging. ► miRNA secretion is altered in age associated diseases.
ESCRT, endosomal sorting complex required for transport; ILV, intraluminal vesicles; miRNA, microRNA; mRNA, messenger RNA; MVB, multivesicular bodies; MSC, mesenchymal stem cell; PM, plasma membrane; Rab, Ras-related in brain; RISC, RNA-induced silencing complex; rRNA, ribosomal RNA; SASP, senescence-associated secretory phenotype; Aging; MicroRNA; Microvesicles; Exosomes; Secretion; Systemic environment
The inflammatory cytokine interleukin-1 (IL1) potentially plays a role in cognitive
deterioration through pathology due to a dementing disorder or due to an aging process. Study of
genetic variants in the IL1 genes has been mostly limited to diseases such as
Alzheimer’s, however, there may be benefit to studying a continuous measure of cognition.
Using data from the Cardiovascular Health Study, we evaluate genetic variation in the genes encoding
inflammatory agonists IL1A and IL1B, and the antagonist IL1RN, with repeated measures of global
cognition (3MS) and processing speed (DSST), using mixed effects models. We found statistically
significant minor allele SNP associations with baseline performance on the 3MS in the
IL1RN gene for Caucasians (rs17042917: beta=0.47,
95%CI=0.09, 0.85, p=0.016; rs4251961: beta=−0.36,
95%CI=−0.13, −0.60, p=0.0027; rs931471: beta=0.39,
95%CI=0.13, 0.65, p=0.0032), and the IL1B gene for African
Americans (rs1143627: beta=1.6, 95%CI=0.48, 2.8; p=0.006 and
rs1143634: beta=2.09, 95%CI=0.39, 3.8; p=0.016). Associations appear
to be weaker in a subgroup with higher education level. Upon removing those diagnosed with dementia,
effect sizes and statistical significance attenuated. These results provide supporting evidence that
genetic variants in IL1 genes may be involved in inflammatory-related lowered
cognition, that higher education may modify genetic predisposition, and that these associations may
be driven by a dementia process.
Interleukin-1; Inflammation; Cognition; Longitudinal study; Genetic epidemiology
Aging in humans is associated with parallel changes in cognition, motivation, and motoric performance. Based on the human aging literature, we hypothesized that this constellation of age-related changes is mediated by the medial prefrontal cortex and that it would be observed in aging mice. Toward this end, we performed detailed assessments of cognition, motivation, and motoric behavior in aging mice. We assessed behavioral and cognitive performance in C57Bl/6 mice aged 6, 18, and 24 months, and followed this with microarray analysis of tissue from the medial prefrontal cortex and analysis of serum cytokine levels. Multivariate modeling of these data suggested that the age-related changes in cognition, motivation, motor performance, and prefrontal immune gene expression were highly correlated. Peripheral cytokine levels were also correlated with these variables, but less strongly than measures of prefrontal immune gene upregulation. To determine whether the observed immune gene expression changes were due to prefrontal microglial cells, we isolated CD11b-positive cells from the prefrontal cortex and subject them to next-generation RNA sequencing. Many of the immune changes present in whole medial prefrontal cortex were enriched in this cell population. These data suggest that, as in humans, cognition, motivation, and motoric performance in the mouse change together with age and are strongly associated with CNS immune gene upregulation.
Aging; prefrontal cortex; motivation; locomotion; gene expression; microarray analysis; RNA sequencing; microglia; cognition
Here we explore association with human longevity of common genetic variation in three major candidate pathways: GH/IGF-1/insulin signaling, DNA damage signaling and repair and pro/antioxidants by investigating 1273 tagging SNPs in 148 genes composing these pathways. In a case-control study of 1089 oldest-old (age 92–93) and 736 middle-aged Danes we found 1 pro/antioxidant SNP (rs1002149 (GSR)), 5 GH/IGF-1/INS SNPs (rs1207362 (KL), rs2267723 (GHRHR), rs3842755 (INS), rs572169 (GHSR), rs9456497 (IGF2R)) and 5 DNA repair SNPs (rs11571461 (RAD52), rs13251813 (WRN), rs1805329 (RAD23B), rs2953983 (POLB), rs3211994 (NTLH1)) to be associated with longevity after correction for multiple testing.
In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes we found 2 pro/antioxidant SNPs (rs10047589 (TNXRD1), rs207444 (XDH)), 1 GH/IGF-1/INS SNP (rs26802 (GHRL)) and 3 DNA repair SNPs (rs13320360 (MLH1), rs2509049 (H2AFX) and rs705649 (XRCC5)) to be associated with mortality in late life after correction for multiple testing.
When examining the 11 SNPs from the case-control study in the longitudinal data, rs3842755 (INS), rs13251813 (WRN) and rs3211994 (NTHL1) demonstrated the same directions of effect (p<0.05), while rs9456497 (IGF2R) and rs1157146 (RAD52) showed non-significant tendencies, indicative of effects also in late life survival. In addition, rs207444 (XDH) presented the same direction of effect when inspecting the 6 SNPs from the longitudinal study in the case-control data, hence, suggesting an effect also in survival from middle age to old age.
No formal replications were observed when investigating the 11 SNPs from the case-control study in 1613 oldest-old (age 95–110) and 1104 middle-aged Germans, although rs11571461 (RAD52) did show a supportive non-significant tendency (OR = 1.162, 95% CI = 0.927–1.457). The same was true for rs10047589 (TNXRD1) (HR = 0.758, 95%CI = 0.543–1.058) when examining the 6 SNPs from the longitudinal study in a Dutch longitudinal cohort of oldest-old (age 85+, N = 563).
In conclusion, the present candidate gene based association study, the largest to date applying a pathway approach, points to potential new longevity loci, but does also underline the difficulties of replicating association findings in independent study populations and thus the difficulties in identifying universal longevity polymorphisms.
human longevity; association study; case-control data; longitudinal data
New blood cells are continually produced from the hematopoietic stem cells (HSCs) that reside in the bone marrow. Throughout the life-span of the organism, this stem cell reservoir sustains life. Although HSCs can persist in vivo longer than one life-span (Harrison, Astle et al. 1978), with aging, HSC regenerative potential diminishes and skewing from lymphopoiesis toward myelopoiesis occurs. The expansion in the HSC pool with aging provides sufficient, yet abnormal, blood production. Examination of gene expression changes in aged HSCs has provided a link between aging and genomic instability. Furthermore, studies on the effects of reactive oxygen species (ROS) on HSC aging has given more insight into the reasons for HSC failure. Understanding of the interactions between niche cells and HSCs and changes in them with aging, may give us insights into the lineage skewing phenotype observed in the aged, and also other immune dysfunctions.
In 2004, the integrated European project GEHA (Genetics of Healthy Ageing) was initiated with the aim of identifying genes involved in healthy ageing and longevity. The first step in the project was the recruitment of more than 2500 pairs of siblings aged 90 years or more together with one younger control person from 15 areas in 11 European countries through a coordinated and standardised effort. A biological sample, preferably a blood sample, was collected from each participant, and basic physical and cognitive measures were obtained together with information about health, life style, and family composition.
From 2004 to 2008 a total of 2535 families comprising 5319 nonagenarian siblings were identified and included in the project. In addition, 2548 younger control persons aged 50–75 years were recruited. A total of 2249 complete trios with blood samples from at least two old siblings and the younger control were formed and are available for genetic analyses (e.g. linkage studies and genome-wide association studies).
Mortality follow-up improves the possibility of identifying families with the most extreme longevity phenotypes. With a mean follow-up time of 3.7 years the number of families with all participating siblings aged 95 years or more has increased by a factor of 5 to 750 families compared to when interviews were conducted. Thus, the GEHA project represents a unique source in the search for genes related to healthy ageing and longevity.
Longevity; Healthy ageing; Nonagenarian sib pairs; Genetics; Europe
The decline in muscular strength with age is disproportionate to the loss in total muscle mass that causes it. Knocking out JP45, an integral protein of the junctional face membrane of the skeletal muscle sarcoplasmic reticulum (SR), results in decreased expression of the voltage-gated Ca2+ channel, Cav1.1; excitation-contraction uncoupling (ECU); and loss of muscle force (Delbono et al., 2007). Here, we show that Cav1.1 expression, charge movement, SR Ca2+ release, in vitro contractile force, and sustained forced running remain stable in male JP45KO mice at 12 and 18 months. They also exhibit the level of ECU reported for 3–4-month mice (Delbono et al., 2007). No further decline at later ages was recorded. Preserved ECC was not related to increased expression of any protein that directly or indirectly interacts with JP45 at the triad junction. However, maintained muscle force and physical performance were associated with ablation of JP45 expression in the brain, spontaneous and significantly diminished food intake and less tendency toward obesity when exposed to a high-fat diet compared to WT. We propose that (1) endogenously generated restriction in food intake overcomes the deleterious effects of JP45 ablation on ECC and skeletal muscle force mainly through downregulation of neuropeptide-Y expression in the hypothalamic arcuate nucleus; and (2) the JP45KO mouse constitutes an invaluable model to examine the mechanisms controlling food intake as well as skeletal muscle function with aging.
Skeletal muscle; aging; JP45; excitation-contraction uncoupling; food intake; caloric restriction