Summary Although many genetic factors and lifestyle interventions are known to affect the mean lifespan of animal populations, the physiological variation displayed by individuals across their lifespans remains largely uncharacterized. Here, we use a custom culture apparatus to continuously monitor five aspects of aging physiology across hundreds of isolated Caenorhabditis elegans individuals kept in a constant environment from hatching until death. Aggregating these measurements into an overall estimate of senescence, we find two chief differences between longer- and shorter-lived individuals. First, though long- and short-lived individuals are physiologically equivalent in early adulthood, longer-lived individuals experience a lower rate of physiological decline throughout life. Second, and counter-intuitively, long-lived individuals have a disproportionately extended “twilight” period of low physiological function. While longer-lived individuals experience more overall days of good health, their proportion of good to bad health, and thus their average quality of life, is systematically lower than that of shorter-lived individuals. We conclude that within a homogeneous population reared under constant conditions, the period of early-life good health is comparatively uniform and the most plastic period in the aging process is end-of-life senescence.
Ageing generates senescent pathologies, some of which cause death. Interventions that delay or prevent lethal pathologies will extend lifespan. Here we identify life-limiting pathologies in Caenorhabditis elegans with a necropsy analysis of worms that have died of old age. Our results imply the presence of multiple causes of death. Specifically, we identify two classes of corpse: early deaths with a swollen pharynx (which we call ‘P deaths'), and later deaths with an atrophied pharynx (termed ‘p deaths'). The effects of interventions on lifespan can be broken down into changes in the frequency and/or timing of either form of death. For example, glp-1 mutation only delays p death, while eat-2 mutation reduces P death. Combining pathology and mortality analysis allows mortality profiles to be deconvolved, providing biological meaning to complex survival and mortality profiles.
While the growth hormone/insulin-like growth factor-1 (GH/IGF-1) pathway plays essential roles in growth and development, diminished signaling via this pathway in model organisms extends lifespan and health-span. In humans, circulating IGF-1 and IGF-binding proteins 3 and 1 (IGFBP-3 and 1), surrogate measures of GH/IGF-1 system activity, have not been consistently associated with morbidity and mortality. In a prospective cohort of independently-living older adults (n = 840, mean age 76.1 ± 6.8 years, 54.5% female, median follow-up 6.9 years), we evaluated the age- and sex-adjusted hazards for all-cause mortality and incident age-related diseases, including cardiovascular disease, diabetes, cancer, and multiple-domain cognitive impairment (MDCI), as predicted by baseline total serum IGF-1, IGF-1/IGFBP-3 molar ratio, IGFBP-3, and IGFBP-1 levels. All-cause mortality was positively associated with IGF-1/IGFBP-3 molar ratio (HR 1.28, 95% CI 1.05–1.57) and negatively with IGFBP-3 (HR 0.82, 95% CI 0.680–0.998). High serum IGF-1 predicted greater risk for MDCI (HR 1.56, 95% CI 1.08–2.26) and composite incident morbidity (HR 1.242, 95% CI 1.004–1.538), whereas high IGFBP-1 predicted lower risk for diabetes (HR 0.50, 95% CI 0.29–0.88). In conclusion, higher IGF-1 levels and bioavailability predicted mortality and morbidity risk, supporting the hypothesis that diminished GH/IGF-1 signaling may contribute to human longevity and health-span.
We have miniaturized standard culture techniques to rear arrays of isolated, individual C. elegans throughout their lives on solid gel media. The resulting apparatus is compatible with brightfield and fluorescent microscopy, enabling longitudinal studies of morphology and fluorescent transgene expression. Our culture system exploits a novel crosslinking reaction between a polyethylene glycol hydrogel and a silicone elastomer to constrain animals to individual “corrals” on the gel surface. These devices are simple to construct on the benchtop with commercially available reagents, and, unlike microfluidic isolation methods, does not rely on micropatterned materials. We demonstrate that this new culture method has negligible effects on the physiology of C. elegans compared to standard culture on agar plates. In addition, RNAi techniques are effective in this system. Finally, the hydrogel–silicone binding chemistry that we developed also allows traditional microfluidic devices to be covalently attached to gel substrates instead of glass.
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SummaryUsing longitudinal data from a cohort of 1349 participants in the Framingham Heart Study, we show that as early as 28–38 years of age, almost 10% of variation in future lifespan can be predicted from simple clinical parameters. Specifically, we found diastolic and systolic blood pressure, blood glucose, weight, and body mass index (BMI) to be relevant to lifespan. These and similar parameters have been well‐characterized as risk factors in the relatively narrow context of cardiovascular disease and mortality in middle to old age. In contrast, we demonstrate here that such measures can be used to predict all‐cause mortality from mid‐adulthood onward. Further, we find that different clinical measurements are predictive of lifespan in different age regimes. Specifically, blood pressure and BMI are predictive of all‐cause mortality from ages 35 to 60, while blood glucose is predictive from ages 57 to 73. Moreover, we find that several of these parameters are best considered as measures of a rate of ‘damage accrual’, such that total historical exposure, rather than current measurement values, is the most relevant risk factor (as with pack‐years of cigarette smoking). In short, we show that simple physiological measurements have broader lifespan‐predictive value than indicated by previous work and that incorporating information from multiple time points can significantly increase that predictive capacity. In general, our results apply equally to both men and women, although some differences exist.
Charge transport across novel DNA junctions has been studied for several decades. From early attempts to move charge across DNA double crossover junctions to recent studies on DNA three-way junctions and G4 motifs, it is becoming clear that efficient cross-junction charge migration requires strong base-to-base electronic coupling at the junction, facilitated by favorable pi-stacking. We review recent progress toward the goal of manipulating and controlling charge transport through DNA junctions.
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