When both genotype and environment are held constant, "chance" variation in the lifespan of individuals in a population is still quite large. Using isogenic populations of the nematode Caenorhabditis elegans we show that, on the first day of adult life, chance variation in the level of induction of a green fluorescent protein (GFP) reporter coupled to a promoter from the hsp-16.2 gene, predicts as much as a four-fold variation in subsequent survival. The same reporter is also a predictor of ability to withstand a subsequent lethal thermal stress. The level of induction of GFP is not heritable and GFP expression levels in other reporter constructs are not associated with differential longevity. HSP-16 alone is probably not responsible for the observed differences in survival but instead is likely reflective of a hidden, heterogeneous, but now quantifiable, physiological state that dictates the ability of the organism to deal with the rigors of living.Chance plays a large and probably ineradicable role in determining variation among individuals in age at death 1,2 . In humans, as well as populations of laboratory animals, 60-90% of the variation in age at death is independent of genotype 3 . In isogenic populations (where genetic variance is essentially zero), under a uniform environment, some individuals die early in life and others live quite long 1,4 . Differences in individual life span of Caenorhabditis elegans can reach as much as 50-fold 4,5 and still have almost as much variation in time of death as does the population of the United States 1,2,6 . Such observations make suspect the popular notion of a "genetic program that regulates longevity" 7 . Instead, geriatric, demographic and evolutionary evidence suggest an alternate paradigm of aging; one that encompasses a rich variety of often highly plastic processes, influenced by genetic, environmental, and stochastic phenomenon 1,2,6 . Here we demonstrate that the ability of individual isogenic worms to respond to stress on the first day of adult life has a large stochastic component and is a major predictor of their subsequent longevity.The optical transparency of C. elegans allows non-invasive visual assessment of living worms without compromising subsequent measurement of longevity. We used a chromosomallyintegrated transgenic strain (TJ375), containing the 400 bp hsp-16.2 promoter coupled to the gene encoding green fluorescent protein (GFP) and encoding no HSP-16.2 product itself (Fig. 1a). This reporter provides an accurate assessment of the total amount of native

Reproduction exacts a price in terms of decreased survival. Our analysis of the interplay between age patterns of fecundity and mortality for individual female med£ies (Ceratitis capitata) revealed that individual mortality is associated with the time-dynamics of the egg-laying trajectory. In a sample of 531 med£ies, we found that each individual has a characteristic rate of decline in egg laying with age. This de¢nes an individual's rate of reproductive exhaustion. This rate was shown to predict subsequent mortality. The larger the remaining reproductive potential, the lower the subsequent mortality. An increased mortality risk was seen in £ies for which egg production declined rapidly early on, irrespective of the level of egg production. Thus, reproductive potential and lifetime are coupled in such a way that those £ies which are able to pro¢t most from an extended life span in terms of increased egg output are indeed likely to live longer.

No abstract

Junctional adhesion molecule-C (JAM-C) plays a key role in the promotion of the reverse transendothelial migration (rTEM) of neutrophils, which contributes to the dissemination of systemic inflammation and to secondary organ damage. During acute pancreatitis (AP), systemic inflammatory responses lead to distant organ damage and typically result in acute lung injury (ALI). Here, we investigated the role of rTEM neutrophils in AP-associated ALI and the molecular mechanisms by which JAM-C regulates neutrophil rTEM in this disorder. In this study, rTEM neutrophils were identified in the peripheral blood both in murine model of AP and human patients with AP, which elevated with increased severity of lung injury. Pancreatic JAM-C was downregulated during murine experimental pancreatitis, whose expression levels were inversely correlated with both increased neutrophil rTEM and severity of lung injury. Knockout of JAM-C resulted in more severe lung injury and systemic inflammation. Significantly greater numbers of rTEM neutrophils were present both in the circulation and pulmonary vascular washout in JAM-C knockout mice with AP. This study demonstrates that during AP, neutrophils that are recruited to the pancreas may migrate back into the circulation and then contribute to ALI. JAM-C downregulation may contribute to AP-associated ALI via promoting neutrophil rTEM.

D receptors control pancreatic inflammation in AP by inhibiting NF-κB activation via a PP2A-dependent Akt signalling pathway.

The results of genome-wide association studies of complex traits, such as life span or age at onset of chronic disease, suggest that such traits are typically affected by a large number of small-effect alleles. Individually such alleles have little predictive values, therefore they were usually excluded from further analyses. The results of our study strongly suggest that the alleles with small individual effects on longevity may jointly influence life span so that the resulting influence can be both substantial and significant. We show that this joint influence can be described by a relatively simple “genetic dose - phenotypic response” relationship.

SummaryProgress in unraveling the genetic origins of healthy aging is tempered, in part, by a lack of replication of effects, which is often considered a signature of falsepositive findings. We convincingly demonstrate that the lack of genetic effects on an aging-related trait can be because of trade-offs in the gene action. We focus on the well-studied apolipoprotein E (APOE) e2 ⁄ 3 ⁄ 4 polymorphism and on lifespan and ages at onset of cardiovascular diseases (CVD) and cancer, using data on 3924 participants of the Framingham Heart Study Offspring cohort. Kaplan-Meier estimates show that the e4 allele carriers live shorter lives than the non-e4 allele carriers (log rank = 0.016). The adverse effect was attributed to the poor survival of the e4 homozygotes, whereas the effect of the common e3 ⁄ 4 genotype was insignificant. The e3 ⁄ 4 genotype, however, was antagonistically associated with onsets of those diseases predisposing to an earlier onset of CVD and a later onset of cancer compared to the none4 allele genotypes. This trade-off explains the lack of a significant effect of the e3 ⁄ 4 genotype on survival; adjustment for it in the Cox regression model makes the detrimental effect of the e4 allele highly significant (P = 0.002). This trade-off is likely caused by the lipidmetabolism-related (for CVD) and nonrelated (for cancer) mechanisms. An evolutionary rationale suggests that genetic trade-offs should not be an exception in studies of aging-related traits. Deeper insights into biological mechanisms mediating gene action are critical for understanding the genetic regulation of a healthy lifespan and for personalizing medical care.

Endocrine functional impairment with insulin resistance was found in patients after AP. Obesity, hyperlipidemia, and diabetes-related symptoms increased the likelihood of developing functional impairment after AP.