Individual Lifetime Research Articles

Sensitive periods during the development and expression of vertebrate sexual signals: A systematic review.

Many sexually selected traits exhibit phenotypic plasticity. Despite a growing appreciation for the ecological context in which sexual selection occurs, and for the role of plasticity in shaping traits associated with local adaptation and divergence, there is an important gap in knowledge about the onset and duration of plasticity in sexual trait expression. Integrating this temporal dimension of plasticity into models of sexual selection informs our understanding of the information conveyed by sexual traits and our predictions related to trait evolution, and is critical in this time of unprecedented and rapid environmental change. We conducted a systematic review of 869 studies to ask how trait modalities (e.g., visual and chemical) relate to the onset and duration of plasticity in vertebrate sexual signals. We show that this literature is dominated by studies of coloration in birds and fish, and most studies take place during the breeding season. Where possible, we integrate results across studies to link physiology of specific trait modalities with the life stage (e.g., juvenile, breeding, or nonbreeding) during which plasticity occurs in well‐studied traits. Limitations of our review included a lack of replication in our dataset, which precluded formal analysis. We argue that the timing of trait plasticity, in addition to environmental context, is critical for determining whether and how various communication signals are associated with ecological context, because plasticity may be ongoing or occur at only one point in an individual's lifetime, and determining a fixed trajectory of trait expression. We advocate for careful consideration of the onset and duration of plasticity when analyzing how environmental variation affects sexual trait expression and associated evolutionary outcomes.

Evaluation of entheseal changes in a modern identified skeletal collection from Inden (Germany)

AbstractThe present study aims to evaluate the frequency of entheseal changes (EC) in a modern skeletal collection from the rural village of Inden, Germany (late 19th–early 20th century), in order to identify general levels of physical activity. The sample is comprised of 66 individuals (51 males and 15 females), whose data on sex, age, and occupation were retrieved from church records. Fourteen fibrous and nineteen fibrocartilaginous entheses of upper and lower limbs were scored in a blind test using two different methods. Grades were converted into binary data, and frequencies of EC were analyzed in each enthesis and in functional complexes by applying a Fisher exact test and a logistic regression. Results showed a higher prevalence for more entheses among female individuals. This does not agree with previous research, but it could be related to the small sample size in this study. More statistically, significant values were found for the relationship between EC and age, which was the main predictor for the presence of EC. However, the percentage of variability that it is explained by age is lower than that found by other studies of European identified collections. This would suggest an interaction with other variables. Regarding occupation, data did not show any clear pattern for the upper limb, whereas for the lower limb, higher frequencies were found for non‐manual workers. Significant values were only found for EC in two entheses of the forearm within the group of manual workers, and one of the feet for non‐manual workers. As with other identified collections, this study was unable to identify distinctive patterns of EC among occupations. This may be due to a combination of different physical activities engaged in or as a result of change of occupation during an individual's lifetime.

Optimal active lifetime investment

Optimal decision-making regarding investments is important. In this study, we examine how an individual aims to find optimal investment policies to overcome a benchmarked opponent during their lifetime. The individual evaluates the trade-off between the achievement of a performance goal and the risk of a shortfall. The dynamic programming method is applied in this study. When the individual's lifetime follows an exponential distribution, the associated Hamilton–Jacobi–Bellman (HJB) equation is an ordinary differential equation, and the explicit optimal policies for several important performance functions are derived. When the lifetime follows a general distribution, the HJB equation is a parabolic partial differential equation, and a Markov chain approximating numerical scheme is presented to estimate the value function. We further illustrate the numerical method when the random lifetime follows the Gompertz–Makeham distribution.

Modelling the impact of increase in sugar prices on dental caries in India.

This study aims to assess the impact of raising the price of sugar and/or sugar-sweetened beverages (SSBs) on caries incidence in the Indian population. A tooth-level decision-analytic model was developed to evaluate a change in caries increment after increasing the price of Sugar and SSBs. The transition of a tooth from a caries-free state to the state of tooth loss in both scenarios was modelled with the help of a Markov model for a time horizon of 63years, ranging from 2021 to 2083 for the 12-year-old population cohort of India. A conceptual framework was designed to implicate the possible effects of an increase in sugar prices on the reduction of caries incidence. Health effects were estimated in terms of the number of carious lesions and tooth-loss in both the scenarios and modelled as a product of the dose-response relationship between sugar intake and caries incidence. The model was thus used to establish the number of caries lesions prevented, and tooth-loss avoided. Uncertainties in the parameters were assessed using probabilistic sensitivity analysis. The Monte Carlo method was used for simulating the results 999 times. A 20% rise in the price of sugar is expected to result in the prevention of an average of 1.32 teeth in a lifetime of an individual and prevent 27.96 million tooth-loss incidents among the population cohort of India that will eventually lead to a saving of INR (₹) 3116.32 billion (US$ 42.69 billion) on account of dental caries treatment. Similarly, increasing-price of SSBs by 20% will lead to a 0.86% reduction in carious teeth incidence in an individual's lifetime. Increasing the cost of sugar and/or SSBs will reduce the daily intake of sugar, which will reduce caries incidence and subsequent progression, thereby preventing caries-attributed tooth-loss and saving treatment costs.

The mutational landscape of human somatic and germline cells.

Over the course of an individual's lifetime, normal human cells accumulate mutations1. Here we compare the mutational landscape in 29 cell types from the soma and germline using multiple samples from the same individuals. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types, but their absolute and relative contributions varied substantially. SBS18, which potentially reflects oxidative damage2, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The rate of mutation was lowest in spermatogonia, the stem cells from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutational processes and may be partially attributable to a low rate of cell division in basal spermatogonia. These results highlight similarities and differences in the maintenance of the germline and soma.

Increasing referral of at-risk women for genetic counseling and BRCA testing using a screening tool in a community breast imaging center.

Genetic evaluation and testing for hereditary breast and ovarian cancer (HBOC) remain suboptimal. The authors evaluated the feasibility of using a screening tool at a breast imaging center to increase HBOC assessment referrals. A brief questionnaire based on the National Comprehensive Cancer Network HBOC genetic counseling referral guidelines was developed and added to the standard intake forms of patients undergoing mammography at a community breast imaging center from 2012 through 2015. Patients who met the criteria in the guidelines were referred for genetic counseling. A total of 34,851 patients were screened during the study period, and 1246 (4%) patients were found to be eligible for referral; 245 of these patients made a genetic counseling appointment, and 142 patients received genetic counseling. Forty patients (28%) had a personal history of breast cancer but were not previously tested. Following counseling, 105 patients were tested for BRCA1/2. Eight patients (8%) tested positive for a pathogenic mutation and nine (9%) had a variant of unknown significance. Although they tested negative, many patients met the criteria to add breast magnetic resonance imaging to their screening due to greater than 20% lifetime breast cancer risk based on their family cancer history. This study led to improved clinical risk management in 67% of the patients who underwent genetic counseling. This study shows that large-scale screening of patients for HBOC syndromes at time of breast imaging is practical and highly feasible. The screening tool identified women with actionable BRCA1/2 mutations and mutation-negative but high-risk women, leading to significant changes in their risk management; these women would otherwise have been missed. Hereditary breast and ovarian cancer (HBOC) caused by pathogenic mutations in breast cancer genes (BRCA1/BRCA2) increase an individual's lifetime risk of getting HBOC. Identifying these high-risk individuals and using proven preventive clinical risk management strategies can significantly reduce their lifetime risk of HBOC. Using an innovative family cancer history questionnaire, 34,000 women were screened at a community breast imaging center, and genetic counseling and testing were provided to eligible women from the screening. Several women at high risk for HBOC were identified and this led to positive clinical risk management changes. These women would have been missed if not for intervention.

Bioenergetic Model Sensitivity to Diet Diversity Across Space, Time and Ontogeny

Consumption is the primary trophic interaction in ecosystems and its accurate estimation is required for reliable ecosystem modeling. When estimating consumption, species’ diets are commonly assumed to be the average of those that occur among habitats, seasons, and life stages which introduces uncertainty and error into consumption rate estimates. We present a case study of a teleost (Yellowfin Bream Acanthopagrus australis) that quantifies the potential error in consumption (in mass) and growth rate estimates when using diet data from different regions and times and ignoring ontogenetic variability. Ontogenetic diet trends were examined through gut content analysis (n = 1,130 fish) and incorporated into a bioenergetic model (the “primary” model) that included diet variability (n = 144 prey sources) and ontogenetic changes in metabolism (1–7 year) to estimate lifetime consumption. We quantified error by building nine model scenarios that each incorporated different spatiotemporal diet data of four published studies. The model scenarios produced individual lifetime consumption estimates that were between 25% lower and 15% higher than the primary model (maximum difference was 53%, range 11.7–17.8 kg). When consumption (in mass) was held constant, differences in diet quality among models caused a several-fold range in growth rate (0.04–1.07 g day–1). Our findings showcase the large uncertainty in consumption rate estimates due to diet diversity, and illustrate that caution is required when considering bioenergetic results among locations, times, and ontogeny.

Epigenetic age prediction in semen - marker selection and model development.

DNA methylation analysis is becoming increasingly useful in biomedical research and forensic practice. The discovery of differentially methylated sites (DMSs) that continuously change over an individual’s lifetime has led to breakthroughs in molecular age estimation. Although semen samples are often used in forensic DNA analysis, previous epigenetic age prediction studies mainly focused on somatic cell types. Here, Infinium MethylationEPIC BeadChip arrays were applied to semen-derived DNA samples, which identified numerous novel DMSs moderately correlated with age. Validation of the ten most age-correlated novel DMSs and three previously known sites in an independent set of semen-derived DNA samples using targeted bisulfite massively parallel sequencing, confirmed age-correlation for nine new and three previously known markers. Prediction modelling revealed the best model for semen, based on 6 CpGs from newly identified genes SH2B2, EXOC3, IFITM2, and GALR2 as well as the previously known FOLH1B gene, which predict age with a mean absolute error of 5.1 years in an independent test set. Further increases in the accuracy of age prediction from semen DNA will require technological progress to allow sensitive, simultaneous analysis of a much larger number of age correlated DMSs from the compromised DNA typical of forensic semen stains.

Developmental ethanol exposure causes central nervous system dysfunction and may slow the aging process in a Drosophila model of fetal alcohol spectrum disorder.

Alcohol is a known teratogen, and developmental exposure to ethanol results in fetal alcohol spectrum disorder (FASD). Children born with FASD can exhibit a range of symptoms including low birth weight, microcephaly, and neurobehavioral problems. Treatment of patients with FASD is estimated to cost 4 billion dollars per year in the United States alone, and 2 million dollars per affected individual's lifetime. We have established Drosophila melanogaster as a model organism for the study of FASD. Here we report that mutations in Dementin (Dmtn), the Drosophila ortholog of the Alzheimer's disease-associated protein TMCC2, convey sensitivity to developmental ethanol exposure, and provide evidence that Dmtn expression is disrupted by ethanol. In addition, we find that flies reared on ethanol exhibit mild climbing defects suggestive of neurodegeneration. Surprisingly, our data also suggest that flies reared on ethanol age more slowly than control animals, and we find that a number of slow-aging mutants are sensitive to developmental ethanol exposure. Finally, we find that flies reared on ethanol showed a persistent upregulation of genes encoding antioxidant enzymes, which may contribute to a reduced rate of central nervous system aging. Thus, in addition to the well-documented negative effects of developmental alcohol exposure on the nervous system, there may be a previously unsuspected neuroprotective effect in adult animals.

Assessing age, breeding stage, and mating activity as drivers of variation in the reproductive microbiome of female tree swallows.

Sexually transmitted microbes are hypothesized to influence the evolution of reproductive strategies. Though frequently discussed in this context, our understanding of the reproductive microbiome is quite nascent. Indeed, testing this hypothesis first requires establishing a baseline understanding of the temporal dynamics of the reproductive microbiome and of how individual variation in reproductive behavior and age influence the assembly and maintenance of the reproductive microbiome as a whole. Here, we ask how mating activity, breeding stage, and age influence the reproductive microbiome. We use observational and experimental approaches to explain variation in the cloacal microbiome of free‐living, female tree swallows (Tachycineta bicolor). Using microsatellite‐based parentage analyses, we determined the number of sires per brood (a proxy for female mating activity). We experimentally increased female sexual activity by administering exogenous 17ß‐estradiol. Lastly, we used bacterial 16S rRNA amplicon sequencing to characterize the cloacal microbiome. Neither the number of sires per brood nor the increased sexual activity of females significantly influenced female cloacal microbiome richness or community structure. Female age, however, was positively correlated with cloacal microbiome richness and influenced overall community structure. A hypothesis to explain these patterns is that the effect of sexual activity and the number of mates on variation in the cloacal microbiome manifests over an individual's lifetime. Additionally, we found that cloacal microbiome alpha diversity (Shannon Index, Faith's phylogenetic distance) decreased and community structure shifted between breeding stages. This is one of few studies to document within‐individual changes and age‐related differences in the cloacal microbiome across successive breeding stages. More broadly, our results contribute to our understanding of the role that host life history and behavior play in shaping the cloacal microbiomes of wild birds.

Plasticity is a locally adapted trait with consequences for ecological dynamics in novel environments.

Phenotypic plasticity is predicted to evolve in more variable environments, conferring an advantage on individual lifetime fitness. It is less clear what the potential consequences of that plasticity will have on ecological population dynamics. Here, we use an invertebrate model system to examine the effects of environmental variation (resource availability) on the evolution of phenotypic plasticity in two life history traits—age and size at maturation—in long‐running, experimental density‐dependent environments. Specifically, we then explore the feedback from evolution of life history plasticity to subsequent ecological dynamics in novel conditions. Plasticity in both traits initially declined in all microcosm environments, but then evolved increased plasticity for age‐at‐maturation, significantly so in more environmentally variable environments. We also demonstrate how plasticity affects ecological dynamics by creating founder populations of different plastic phenotypes into new microcosms that had either familiar or novel environments. Populations originating from periodically variable environments that had evolved greatest plasticity had lowest variability in population size when introduced to novel environments than those from constant or random environments. This suggests that while plasticity may be costly it can confer benefits by reducing the likelihood that offspring will experience low survival through competitive bottlenecks in variable environments. In this study, we demonstrate how plasticity evolves in response to environmental variation and can alter population dynamics—demonstrating an eco‐evolutionary feedback loop in a complex animal moderated by plasticity in growth.

Inbreeding reduces fitness of seed beetles under thermal stress.

Human‐induced environmental change can influence populations both at the global level through climatic warming and at the local level through habitat fragmentation. As populations become more isolated, they can suffer from high levels of inbreeding, which contributes to a reduction in fitness, termed inbreeding depression. However, it is still unclear if this increase in homozygosity also results in a corresponding increase in sensitivity to stressful conditions, which could intensify the already detrimental effects of environmental warming. Here, in a fully factorial design, we assessed the life‐long impact of increased inbreeding load and elevated temperature on key life history traits in the seed beetle, Callosobruchus maculatus. We found that beetles raised at higher temperatures had far reduced fitness and survival than beetles from control temperatures. Importantly, these negative effects were exacerbated in inbred beetles as a result of increased inbreeding load, with further detrimental effects manifesting on individual eclosion probability and lifetime reproductive success. These results reveal the harmful impact that increasing temperature and likelihood of habitat fragmentation due to anthropogenetic changes in environmental conditions could have on populations of organisms worldwide.

Contributions of evolutionary anthropology to understanding climate-induced human migration.

Humans are able to thrive in a multitude of ecological and social environments, including varied environments over an individual lifetime. Migration—leaving one place of residence for another—is a central feature of many people's life histories, and environmental change goes hand‐in‐hand with migration, both in terms of cause and consequence. Climate change has amplified this connection between environment and migration, with the potential to profoundly impact millions of lives. Although climate‐induced migration has been at the forefront of other disciplines in the social sciences, evolutionary anthropologists (EAs) have given it little attention. In this paper we draw upon existing literature and contribute our EA perspective to present a framework for analyzing climate‐induced migration that utilizes theoretical approaches from a variety of social science disciplines. We focus on three overlapping dimensions—time, space, and severity—relevant to understanding the impact of climate change on human migration. We apply this framework to case studies from North America of people impacted by climate change and extreme weather events, including hurricanes, droughts, rising sea‐levels, and wildfires. We also consider how access to both economic and social resources influence decisions regarding migration. Research focused on climate‐induced human migration can benefit equally from the addition of EA perspectives and a more interdisciplinary theoretical approach.

Abstract 2114: Horvath clock as a predictor of cancer risk in LFS patients

Abstract Li-Fraumeni syndrome (LFS) is an autosomal dominantly inherited cancer predisposition syndrome associated with germline mutations of the TP53 tumor suppressor gene. TP53 mutation carriers are susceptible to a wide range of cancers that occur at strikingly earlier age of onset than their sporadic counterparts. The lifetime cancer risk in TP53 mutation carriers is estimated to be ~73% for males and approaching 100% in females. Although improved survival outcomes have been demonstrated for carriers undergoing intense clinical surveillance, there is continued interest in identifying new environmental, genetic, and epigenetic risk factors that could improve our ability to predict disease onset and outcome. A number of studies have demonstrated age-associated DNA methylation (DNAm) changes at specific CG dinucleotides and that these changes can be combined into epigenetic age predictors to estimate chronological age. Deviation of chronological and predicted age have been associated with age-associated illnesses such as metabolic disease and cancer. For a given chronological age, older epigenetic age is presumed to indicate poorer health. An epigenetic profile defining the DNA methylation age (DNAm age) of an individual has been suggested to be a biomarker of aging, and thus possibly providing a tool for assessment of health and mortality. Our goal was to test whether DNAm age could be a possible predictor of cancer risk in LFS patients. We applied the DNA age calculator (http://dnamage.genetics.ucla.edu/) (Horvath 2013) to DNA methylation profiles derived from lymphocytes extracted from 157 LFS patients' blood samples using the Illumina HumanMethylation450 BeadChip. While a correlation of DNAm age and actual age was observed in both ‘normal' and LFS patients, the latter showed significant deviations (differences between DNAm age and chronological age). Moreover, the extent of deviations seems selectively associated with two distinct age groups (0-5 years and 20-50 years). Remarkably, this bimodal DNAm age profile shows striking resemblance to the epidemiologically characterized age dependency of LFS cancers (Amadou, 2018). Individuals with germline mutant or germline wild-type TP53 and no cancer showed no epigenetic age acceleration whereas individuals who were carriers of mutant TP53 who developed cancer showed accelerated epigenetic aging. Our preliminary results suggest that DNAm age is a dynamic, real-time correlate of patient-specific cancer risk in LFS. Further, the age dependent deviations suggest that the cancer risk profiles derived from Horvath signatures are dynamic and reflect the changes in cancer risk throughout an individual's lifetime, and could be used as a predictor of cancer onset in TP53 mutation carriers. Citation Format: Malgorzata Pienkowska, Nardin Samuel, Sanaa Choufani, Vallijah Subasri, Nish Patel, Rosanna Weksberg, Ran Kafri, David Malkin. Horvath clock as a predictor of cancer risk in LFS patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2114.

Risk stratification in men with a negative prostate biopsy: an interim analysis of a prospective cohort study.

To investigate whether a risk score for prostate cancer (PCa) lifetime risk can be used to optimise triaging of patients with a negative prostate biopsy, but under sustained suspicion of PCa. In this prospective clinical study, we included, and risk scored patients who had a PCa-negative transrectal ultrasonography (TRUS)-guided prostate biopsy, but elevated prostate-specific antigen (PSA), a suspicious prostate digital rectal examination and/or a positive family history (FH) of PCa. The risk score estimated individual lifetime risk of PCa, based on a polygenic risk score (33 single nucleotide polymorphisms), age, and FH of PCa. Patients were followed, under urological supervision, for up to 4years with annual controls, always including PSA measurements. Multiparametric magnetic resonance imaging (mpMRI) and/or prostate biopsy was performed at selected annual controls depending on risk score and at the urologist's/patient's discretion, which means that the follow-up differed based on the risk score. We included 429 patients. After risk scoring, 376/429 (88%) patients were allocated to a normal-risk group (<30% PCa lifetime risk) and 53/429 (12%) to a high-risk group (≥30% PCa lifetime risk). The high-risk group had significantly different follow-up, with more biopsy and mpMRI sessions compared to the normal-risk group. PCa was detected in 89/429 (21%) patients, with 67/376 (18%) patients diagnosed in the normal-risk group and 22/53 (42%) in the high-risk group. There was no statistically significant difference in the cumulative incidence of PCa between the normal-risk group and the high-risk group after 4years of follow-up. Currently, 67/429 (16%) patients are still being followed in this ongoing study. In a 4-year perspective, our PCa lifetime risk score did not demonstrate significant prognostic value for triaging patients, with a negative TRUS-guided biopsy and sustained suspicion of PCa.

Ateroesclerosis

Atherosclerosis is the pathogenic process that underlies the different clinical manifestations of cardiovascular disease. Through the progressive reduction of the diameter of the vessel lumen or the sudden development of a thrombus, the normal blood flow to the different tissues is obstructed, which can affect the heart (ischaemic heart disease), brain (stroke) or limbs (peripheral arterial disease). Atherosclerosis is now considered a chronic inflammatory process that precedes clinical manifestations by several decades. The initial process that promotes plaque development is the disruption of endothelial integrity and function. Plaque formation is caused by the accumulation of lipid particles in predisposed areas and is facilitated by processes of inflammation, necrosis, fibrosis, and calcification. Its development is closely linked to prolonged exposure to certain risk factors, which interact with other environmental factors, genes, and individual susceptibility. The disease usually progresses indolently over the individual's lifetime, until the progression of plaque causes it to destabilise and rupture, leading to ischaemia of the affected organ.

Estimating Aggregate Environmental Risk Score in Psychiatry: The Exposome Score for Schizophrenia.

To understand the role of environment in the pathoetiology of psychosis spectrum disorders, research has thus far mainly investigated the effects of single exposures in isolation, such as the association between cannabis use and schizophrenia. However, this approach fails to acknowledge the complexity of the exposome, which represents the totality of the environment involving many exposures over an individual's lifetime. Therefore, contemporary research adopting the exposome paradigm has aimed at capturing the combined effect of different environmental exposures by utilizing an aggregate environmental vulnerability score for schizophrenia: the exposome score for schizophrenia. Here, we attempt to provide a comprehensive overview of studies applying the exposome score for schizophrenia. First, we describe several approaches estimating exposomic vulnerability for schizophrenia, which falls into three categories: simple environmental sum scores (sum of dichotomized exposures), meta-analysis-based environmental risk score (sum scores weighted by estimates from meta-analyses), and the exposome score (sum score weighted by estimates from an analysis in an independent training dataset). Studies show that the exposome score for schizophrenia that assumes interdependency of exposures performs better than scores that assume independence of exposures, such as the environmental sum score and the meta-analysis-based environmental risk score. Second, we discuss findings on the pluripotency of the exposome score for schizophrenia and summarize findings from gene-environment studies using the exposome score for schizophrenia. Finally, we discuss possible scientific, clinical, and population-based applications of exposome score for schizophrenia, as well as limitations and future directions for exposome research to understand the etiology of psychosis spectrum disorders.

Health-related quality of life and economic burden of prurigo nodularis

Prurigo nodularis (PN) is an understudied, pruritic inflammatory skin disease. Little is known about the effect of PN on quality of life and its associated economic burden. To quantify the impact of PN on quality of life and its economic implications. A cohort study of PN patients (n=36) was conducted using the Health Utilities Index Mark 3 questionnaire. Control data from US adults (n=4187) were obtained from the 2002-2003 Joint Canada/United States Survey of Health. Quality-adjusted life year loss and economic costs were estimated by comparing the Health Utilities Index Mark 3 scores of the PN patients with those of the controls. The PN patients had lower overall health performance compared to the controls, (mean±SE, 0.52±0.06 vs 0.86±0.003, respectively, P<.001). In multivariable regression, PN was found to be associated with worse health performance (coefficient -0.34, 95% CI [-0.46 to -0.23]), most prominent in the pain subdomain (coefficient -0.24, 95% CI [-0.35 to -0.13]). This correlated to an average of 6.5 lifetime quality-adjusted life years lost per patient, translating to an individual lifetime economic burden of $323,292 and a societal burden of $38.8 billion. These results demonstrate that PN is associated with significant quality-of-life impairment, similar to the level of other chronic systemic conditions. PN is also associated with a substantial individual economic burden, emphasizing the necessity of research on effective treatment options.

Aging as a consequence of selection to reduce the environmental risk of dying

Each animal in the Darwinian theater is exposed to a number of abiotic and biotic risk factors causing mortality. Several of these risk factors are intimately associated with the act of energy acquisition as such and with the amount of reserve the organism has available from this acquisition for overcoming temporary distress. Because a considerable fraction of an individual's lifetime energy acquisition is spent on somatic maintenance, there is a close link between energy expenditure on somatic maintenance and mortality risk. Here, we show, by simple life-history theory reasoning backed up by empirical cohort survivorship data, how reduction of mortality risk might be achieved by restraining allocation to somatic maintenance, which enhances lifetime fitness but results in aging. Our results predict the ubiquitous presence of senescent individuals in a highly diverse group of natural animal populations, which may display constant, increasing, or decreasing mortality with age. This suggests that allocation to somatic maintenance is primarily tuned to expected life span by stabilizing selection and is not necessarily traded against reproductive effort or other traits. Due to this ubiquitous strategy of modulating the somatic maintenance budget so as to increase fitness under natural conditions, it follows that individuals kept in protected environments with very low environmental mortality risk will have their expected life span primarily defined by somatic damage accumulation mechanisms laid down by natural selection in the wild.

Review of cohort diversity in the development and validation of cancer risk assessment models.

e18570 Background: Multiple validated models have been proposed to quantify an individual's lifetime risk of breast and colon cancer. However, an evaluation of the race and ethnicity of the cohorts studied in the development and validation of each of these models has not been reviewed. Predicting cancer risks accurately in Black, Indigenous and People of Color (BIPOC) can be crucial in helping to reduce cancer mortality rates and improving access to preventative care for these individuals. Methods: A literature search was conducted to identify published development and validation studies for the following cancer risk assessment models: Breast Cancer Surveillance Consortium (BCSC) Risk Calculator, Tyrer-Cuzick, Gail, Claus, CanRisk/BOADICEA, BRCAPRO and MMRPRO. Articles included were identified through review of a number of electronic databases and websites for the cancer risk prediction models. Authors were contacted for data not readily available through literature search. Results: A total of 15 development studies and 19 validation studies of the cancer risk prediction models were reviewed for the seven models listed above. Out of the 19 validation studies, seven were internal and twelve were external validation studies. 80% (12/15) of development studies and 68% (13/19) of validation studies did not include information on racial and ethnic composition of the cohorts. After obtaining additional information from authors, 53% (8/15) of the development studies were conducted solely in non-Hispanic White (NHW) cohort. The development cohorts ranged from 50%-100% NHW, 0%-7% non-Hispanic Black (NHB), 0%-8% Hispanic/Latinx, 0%-3% Asian and 0%-1% Indigenous participants. 58% (7/12) of external validation studies included ethnically and racially diverse populations compared to 14% (1/7) of internal validation studies. The BCBS, Gail, BRCAPRO and MMRPRO models were the only models with external validation studies conducted in ethnically or racially diverse populations. Overall, the model that had the most diverse cohort for its development and internal validation studies was the BCBS with 70% NHW, 6.7% NHB, 7.5% Hispanic/Latinx, 2.7% Asian, 0.8% Indigenous and 11.5% mixed/other ethnicities. Conclusions: The majority of the models reviewed did not have ethnically or racially diverse populations in their development and validation cohorts. Awareness of the under-representation of ethnically and racially diverse populations in these models is an important precaution for extrapolating data when using these models in medical decision making for BIPOC individuals. Although several barriers exist for participation of BIPOC individuals in clinical studies, these findings highlight the critical, yet unmet need for the development and use of appropriate cancer risk models in racially and ethnically diverse populations as a means to reduce health-related disparities.