The relative insensitivity of lifespan to environmental factors constitutes compelling evidence that the physiological decline associated with aging derives primarily from the accumulation of intrinsic molecular and cellular side-effects of metabolism. Here we model that accumulation starting from a biologically based interpretation of the way in which those side-effects interact. We first validate this model by showing that it very accurately reproduces the distribution of ages at death seen in typical populations that are well protected from age-independent causes of death. We then exploit the mechanistic basis of this model to explore the impact on lifespans of interventions that combat aging, with an emphasis on interventions that repair (rather than merely retard) the direct molecular or cellular consequences of metabolism and thus prevent them from accumulating to pathogenic levels. Our results strengthen the case that an indefinite extension of healthy and total life expectancy can be achieved by a plausible rate of progress in the development of such therapies, once a threshold level of efficacy of those therapies has been reached.
Aging; Damage; Intervention; Lifespan; Longevity escape velocity; Rejuvenation; Reserve; Simulation
“Physiological” aging as well as early and progressive cardiac hypertrophy may affect action potential (AP) pattern, contractile function, and Ca2+ handling. We hypothesize that contractile function is disturbed in hypertrophy from early stages and is differently affected in aged myocardium. In vivo function, cardiomyocyte contractile behavior and APs were compared in Wistar-Kyoto (WIS) rats and spontaneously hypertensive rats (SHR) at different ages and degrees of hypertrophy (3–4, 9–11, 20–24 months). Post-rest (PR) behavior was used to investigate the relative contribution of the sarcoplasmic reticulum (SR) and the Na/Ca exchanger (NCX) to cytosolic Ca2+ removal. APs were recorded by whole-cell current-clamp and sarcomere shortening by video microscopy. Cyclopiazonic acid was used to suppress Ca2+ ATPase (SERCA) function. Heart weight/body weight ratio was increased in SHR versus WIS within all age groups. Myocyte steady state (SS) shortening amplitude was reduced in young SHR versus WIS. Aging led to a significant decay of SS contractile amplitude and relengthening velocity in WIS, but the PR potentiation was maintained. In contrast, aging in SHR led to a decrease of PR potentiation, while SS contraction and relengthening velocity increased. APD50% was always prolonged in SHR versus WIS. With aging, APD50% increased in both WIS and SHR, but was still shorter in WIS. However, in old WIS the late AP portion (APD90%) was prolonged. Ca2+ handling and AP properties are disturbed progressively with aging and with increasing hypertrophy. Decreased amplitude of shortening and velocity of relengthening in aged WIS may be attributed to reduced SERCA function. In SHR, an increase in SR leak and shift towards transmembraneous Ca handling via NCX may be responsible for the changes in contractile function. A prolonged APD90% in aged WIS may be an adaptive mechanism to preserve basal contractility. Therefore, the effects on contractile parameters and AP are different in hypertrophy and aging.
Aging; Hypertrophy; Contractile function; SR function; Na/Ca exchanger; Ryanodine receptor
Our previous studies demonstrated a significant decline in brain function and behavior in Fischer 344 (F344) rats with age. The present study was designed to test the hypothesis that dysregulation in calcium homeostasis (as assessed through 45Ca flux) may contribute to the increase in age-related vulnerability to oxidative stress in brain regions, and result in a deficit in behavior-mediated signaling. Crude membrane (P-2) and more purified synaptosomal fractions were isolated from the striatum, hippocampus, and frontal cortex of young (6 months) and old (22 months) F344 rats and were assessed for calcium flux and extracellular-regulated kinase activity 1 (ERK) under control and oxidative stress conditions induced by low dose hydrogen peroxide (final concentration 5 μM). The level of oxidative stress responses was monitored by measuring reactive oxygen species (ROS) and glutathione (GSH). The results showed a significant difference in oxidative stress responses between young and old rats in evaluated brain regions. Old rats showed higher sensitivity to oxidative stress than young rats. The present findings show the differential effects of oxidative stress on calcium flux in brain regions with age that are dependent upon the brain areas examined and the fraction assessed. The accumulation of ROS and the decrease in GSH in the frontal cortex were sufficient to decrease ERK activity in old rats. This is the first study, to our knowledge, that demonstrates age-related differential sensitivity to oxidative stress expressed as a function of behavior-mediated signaling and stress levels among different fractions isolated from brain regions controlling behavior.
P-2 fraction; Synaptosomes; Calcium; Glutathione; Extracellular signal-regulated kinase
The homocysteine level is considered to be a product of genetic and lifestyle interactions, mainly mutated methylenetetrahydrofolate reductase (MTHFR) and the intake of folate, vitamin B12 and pyridoxine, and their blood levels. Physical activity has been associated with lower homocysteine levels in some population studies, especially among elderly subjects. To further elucidate the observed association between homocysteine and physical activity, while accounting for the effect of the MTHFR C677T genotype, and of plasma levels of folate and B12 vitamins, a cross-sectional study of 620 males and females, aged 70.5 ± 6.8 years, was carried out. Information on lifestyle habits was collected and laboratory examinations of 12-h fasting total plasma homocysteine, folate, and vitamin B12, as well as DNA analysis for MTHFR C677T variant, were performed. Median total homocysteine values were 11.4 μmol/l for males and 9.4 for females; p < 0.001. Smoking and ethnic origin were not found to be associated with homocysteine levels. Physically active subjects had significantly lower total homocysteine levels when adjusted for sex (p = 0.01). Significant inverse correlations were found between body mass index, plasma folate, B12 and homocysteine levels. Homocysteine levels of the CC, CT and TT genotypes were 9.7, 10.6 and 10.2 μmol/l, respectively (p = 0.002, controlling for sex). In a multiple linear regression model, a sedentary lifestyle increased homocysteine levels by 7% as compared to an active one (p = 0.03) controlling for sex, age, body mass index, folate, vitamin B12, and C677T genotype, all of which were also found to be significantly associated with homocysteine levels. Any level of physical activity was found to be independently associated with lower homocysteine levels in an elderly population, controlling for MTHFR genotype, plasma B-vitamins, age, sex, smoking and BMI. This study emphasizes the importance of maintaining a physically active lifestyle in the elderly.
B vitamins; Elderly; Homocysteine; Lifestyle; MTHFR genotyping; Physical activity
Our purpose was to examine the effects of age and gender on physical performance. We assessed a one-hour swimming performance and participation of 4,271 presumably healthy men and women, aged 19–91 years, from the 2001–2003 United States Masters Swimming long-distance (1 h) national competition. The decline in performance with increasing age was found to be quadratic rather than linear. The equation which best fit variation in 1 h swimming distance in meters (m) according to variations in age in years (y) in men was: distance (m) = 4058 + 2.18 age−0.29 age (http://www.acsmmsse.org/pt/re/msse/positionstandards.htm;jsessionid=DiRVACC7YS3mq27s5kV3vwpEVSokmmD1ZJLC7pdnol3KcfoSu0t!1096311956!-949856145!9001!-1), with the same equation for women except that 380 m needed to be subtracted from the calculated value at all ages (about a 10% difference). There was a large overlap in performance between men and women. The overall mean decline in performance with age was about 50% and was parallel in men and women. The mean difference in distance for a 1-year increment in age was −9.7 m at 21 y of age, −21.3 m at 40 y, and −44.5 m at 80 y. Far greater declines of about 96% in numbers participating with advanced age (80 y and over, 4% of peak numbers) were observed than in the 40–49 y age group. In conclusion, the declines in performance were parallel in men and women at all ages, and the 1-year age-related declines in performance were about twice as great at 40 y and more than four-times as great at 80 y than at 20 y of age, with even greater age-related declines in participation being noted for both men and women.
Aging; Physical performance; Physical activity; Exercise; Swimming
Murine models that mimic the neuropathology of Alzheimer’s disease (AD) have the potential to provide insight into the pathogenesis of the disease and lead to new strategies for the therapeutic management of afflicted patients. We used magnetic resonance imaging (MRI), design-based stereology, and high performance liquid chromatography (HPLC) to assess the age-related neuropathology in double transgenic mice that overexpress two AD-related proteins—amyloid precursor protein (APP) and presenilin 1 (PS1)—and age- and gender-matched wild-type (WT) controls. In mice ranging in age from 4–28 months, total volumes of the hippocampal formation (VHF) and whole brain (Vbrain) were quantified by the Cavalieri-point counting method on a systematic-random sample of coronal T2-weighted MRI images; the same stereological methods were used to quantify VHF and Vbrain after perfusion and histological processing. To assess changes in AD-type beta-amyloid (Aβ) plaques, sections from the hippocampal formation and amylgdaloid complex of mice aged 5, 12, and 15 months were stained by Congo Red histochemistry. In aged mice with large numbers of amyloid plaques, systematic-random samples of sections were stained by GFAP immunocytochemistry to assess gender and genotype effects on total numbers of astrocytes. In addition, levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT) and 5-HT metabolites were assayed by HPLC in fresh-frozen samples from neocortex, striatum, hippocampus, and brainstem. We confirmed age-related increases in amyloid plaques, beginning with a few plaques at 5 months of age and increasing densities by 12 and 15 months. At 15 months of age, there were robust genotype effects, but no gender effects, on GFAP-immunopositive astrocytes in the amygdaloid complex and hippocampus. There were no effects on monoamine levels in all brain regions examined, and no volume changes in hippocampal formation or whole brain as quantified on either neuroimages or tissue sections. Strong correlations were present between volume estimates from MRI images and histological sections, with about 85% reduction in mean VHF or mean Vbrain between MRI and processed histological sections. In summary, these findings show that the double transgenic expression of AD-type mutations is associated with age-related increases in amyloid plaques and astrocytosis; however, this model does not recapitulate the cortical atrophy or neurochemical changes that are characteristic of AD.
MRI; Alzheimer’s disease; Hippocampal formation; Amygdala; Unbiased stereology
A review of the literature in both animals and humans reveals that changes in sex hormone have often been associated with changes in behavioral and mental abilities. Previously published research from our laboratory, and others, provides strong evidence that P300 (latency) event-related potential (ERP), a marker of neuronal processing speed, is an accurate predictor of early memory impairment in both males and females across a wide age range. It is our hypothesis, given the vast literature on the subject, that coupling growth hormones (insulin-like growth factor-I, (IGF-I) and insulin-like growth factor binding protein 3 (IGF-BP3)), P300 event-related potential and test of variables of attention (TOVA) are important neuroendocrinological predictors of early cognitive decline in a clinical setting. To support this hypothesis, we utilized structural equation modeling (SEM) parameter estimates to determine the relationship between aging and memory, as mediated by growth hormone (GH) levels (indirectly measured through the insulin-like growth factor system), P300 latency and TOVA, putative neurocognitive predictors tested in this study. An SEM was developed hypothesizing a causal directive path, leading from age to memory, mediated by IGF-1 and IGF-BP3, P300 latency (speed), and TOVA decrements. An increase in age was accompanied by a decrease in IGF-1 and IGF-BP3, an increase in P300 latency, a prolongation in TOVA response time, and a decrease in memory functioning. Moreover, independent of age, decreases in IGF-1 and IGF-BP3, were accompanied by increases in P300 latency, and were accompanied by increases in TOVA response time. Finally, increases in P300 latency were accompanied by decreased memory function, both directly and indirectly through mediation of TOVA response time. In summary, this is the first report utilizing SEM to reveal the finding that aging affects memory function negatively through mediation of decreased IGF-1 and IGF-BP3, and increased P300 latency (delayed attention and processing speed).
Structural equation modeling (SEM); P300 latency; TOVA; IGF-1; IGF-BP3; Age and memory
Exposure to 56Fe particles produces changes in dopaminergic function and in dopamine-dependent behaviors, including amphetamine-induced conditioned taste aversion (CTA) learning. Because many of these changes are characteristic of the changes that accompany the aging process, the present study was designed to determine whether or not there would be an interaction between age and exposure to 56Fe particles in the disruption of an amphetamine-induced CTA. One hundred and forty F-344 male rats 2-, 7-, 12-, and 16-months old, were radiated with 56Fe particles (0.25–2.00 Gy, 1 GeV/n) at Brookhaven National Laboratory. Three days following irradiation, the rats were tested for the effects of radiation on the acquisition of a CTA produced by injection of amphetamine (3 mg/kg, i.p.). The main effect of age was to produce a significant decrease in conditioning day sucrose intake; there was no affect of age on the acquisition of the amphetamine-induced CTA. Exposing rats to 56Fe particles disrupted the acquisition of the CTA produced by injection of amphetamine only in the 2-month-old rats. These results do not support the hypothesis of an interaction between age and exposure to 56Fe particles in producing a disruption of amphetamine-induced CTA learning. As such, these results suggest that the aging produced by exposure to 56Fe particles may be endpoint specific.
56Fe particles; Aging; Amphetamine; Conditioned taste aversion; F-344 rats
Microarray-based comparisons of long-lived and normal mouse strains represent a promising approach for dissecting the basis of lifespan extension in higher organisms. Recently, Boylston et al. (2006) generated a genome-wide data set that allowed expression levels of Snell (Pit1dw/dw) and Ames (Prop1df/df) long-lived mice to be compared with age-matched control mice across different ages (6–24 months). Longevity-associated genes were identified as those genes exhibiting differential expression between long-lived and normal mice at every age examined. In this communication, an alternative approach to identifying longevity-associated genes is suggested and applied to the data sets considered by Boylston et al. (2006). Longevity-associated genes are defined as those exhibiting significant genotype-by-age interaction with respect to expression levels of long-lived and normal mice, and a total of 63 longevity-associated genes are identified. This approach may lend greater confidence to the inference that expression of identified genes specifically underlies aging differences between long-lived and normal genotypes.
Aging; Ames; Dwarf; Lifespan; Microarray; Pit1dw; Prop1df; Snell
Effects of treatment with DHEA (0.2 or 1.0 mg/kg body weight for 7 days) on oxidative energy metabolism of rat liver mitochondria from old (18–24 month old) and young (8–10 weeks old) male albino rats belonging to Charles-Foster strain were examined. Treatment with 1.0 mg DHEA resulted in increased body weights of the young rats without change in the liver weight. In the old animals the liver weight increased progressively with increasing dose of DHEA without affecting body weight. The state 3 respiration rates in liver mitochondria from old animals were, in general, lower than those in the young rats. The state 3 and state 4 respiration rates increased following DHEA treatment in dose-dependent manner bringing them close to values for young animals or beyond that with the effect being more pronounced at 1.0 mg dose. Treatment with DHEA also stimulated state 3 and state 4 respiration rates in young rats in dose-dependent manner. Contents of cytochrome aa3, b and c + c1 increased significantly in old animals in dose-dependent manner. In the young rats the lower dose (0.2 mg) of DHEA was more effective in bringing about a maximum increase in the contents of the cytochromes; the effect declined at the higher dose (1.0 mg). DHEA treatment also stimulated the mitochondrial ATPase activity in the old as well as in the young rats. The dehydrogenases activities were considerably low in the old rats compared to the values for the young animals. Treatment with DHEA stimulated dehydrogenases activities in old rats in dose-dependent manner bringing them close to values for the young animals or beyond. Treatment with lower dose (0.2 mg) of DHEA maximally stimulated dehydrogenases activities in young animals.
ATPase activity; cytochromes; dehydroepiandrosterone (DHEA); dehydrogenases; liver mitochondria; oxidative energy metabolism
In order to understand the basic mechanisms underlying the organismic aging process, considerable efforts have been devoted in the last half-century to biochemical (enzyme activity) alterations in specific tissues and organs of various organisms associated with aging. When a decline in enzyme activities with age has been found in a study, especially for key enzymes such as antioxidant enzymes, the results have often been interpreted as a cause for the aging of the entire body. Retrospectively, however, these changes turned out to be so variable—depending on species, strains and sexes of animals—that the interpretation of these results in general terms of aging became invalid. Further, unlike the prediction for the whole human body, many enzyme activities in a vital organ, such as the liver, remained unchanged, as long as the old subjects remained healthy. However, enzyme activities in old animals and humans are often more susceptible to morbidities and frailties, which themselves are often accompanied by infections and malnutrition. Despite the rather stable enzyme functions in the liver with age, a distinct and progressive decline in the lateral diffusion coefficient of proteins of hepatocyte plasma membranes has been demonstrated by fluorescence recovery after photobleaching (FRAP), which was implicated as the cause for the decline of hepatocyte functions such as ouabain (and taurocholate) hepatic uptake and their eventual biliary excretion. Since a similar decline in protein diffusion coefficients was observed in brain and muscle cells, it is likely that these changes are occurring in common with many cell types of the body, thus causing a delay in transmembrane transport of endogenous and exogenous substances whose transports are mediated by membrane proteins. In attempts to prolong the life spans of animals other than by calorie restriction, but instead using deprenyl or tetrahydrocurcumin, works by the author and coworkers are introduced and discussed. Despite limited success along these lines thus far, further attempts are encouraged, primarily to understand the mechanisms underlying organismic aging processes and to find a practical way to prolong the health span of the elderly.
aging rodents; altered enzymes; antioxidant enzymes; (-)deprenyl; hepatic microsomal P-450 functions; maximal seizure response; protein lateral diffusion coefficients of cell surface membranes; sex- and strain-related differences; tetrahydrocurcumin
We considered a Gompertzian model for the population dynamics of Eisenia andrei case-cohorts in artificial OECD soil under strictly controlled conditions. The earthworm culture was kept between 18 and 22°C at a constant pH of 5.0. In all, 77 lumbricids were carefully followed for almost 9 years, until the oldest died. The Eisenia median longevity is 4.25 years and the oldest specimen was 8.73 years. Eisenia cocoons were hand-sorted every 3 weeks, washed in distilled water, placed in Petri dishes, and counted. Regular removal did not reduce breeding. Each fertile cocoon contained on average two or three embryos. The failure rates (mortality and infertility percentages) are smooth power functions where the rate at time (n + 1) captured most of the phenomenology of the previous rate at time n, as expected by the considered law, but not at both the beginning and the end of this long-term laboratory study.
Allometric scaling; Body-mass values; Cocoon fertility; Eisenia; Failure rates; Gompertz