Clarifying the biological and statistical assumptions of cross-sectional biological age predictors: an elaborate illustration using synthetic and real data.

BACKGROUND: There is divergence in the rate at which people age. The concept of biological age is postulated to capture this variability, and hence to better represent an individual's true global physiological state than chronological age. Biological age predictors are often generated based on cross-sectional data, using biochemical or molecular markers as predictor variables. It is assumed that the difference between chronological and predicted biological age is informative of one's chronological age-independent aging divergence ∆. METHODS: We investigated the statistical assumptions underlying the most popular cross-sectional biological age predictors, based on multiple linear regression, the Klemera-Doubal method or principal component analysis. We used synthetic and real data to illustrate the consequences if this assumption does not hold. RESULTS: The most popular cross-sectional biological age predictors all use the same strong underlying assumption, namely that a candidate marker of aging's association with chronological age is directly informative of its association with the aging rate ∆. We called this the identical-association assumption and proved that it is untestable in a cross-sectional setting. If this assumption does not hold, weights assigned to candidate markers of aging are uninformative, and no more signal may be captured than if markers would have been assigned weights at random. CONCLUSIONS: Cross-sectional methods for predicting biological age commonly use the untestable identical-association assumption, which previous literature in the field had never explicitly acknowledged. These methods have inherent limitations and may provide uninformative results, highlighting the importance of researchers exercising caution in the development and interpretation of cross-sectional biological age predictors.

Actuarial Aging Rates in Human Cohorts.

Aging rate is an important characteristic of human aging. Attempts to measure aging rates through the Gompertz slope parameter lead to a conclusion that actuarial aging rates were stable during the most of the 20th century, but recently demonstrate an increase over time in the majority of studied populations. These findings were made using cross-sectional mortality data rather than by the analysis of mortality of real birth cohorts. In this study we analyzed historical changes of actuarial aging rates in human cohorts. The Gompertz parameters were estimated in the age interval 50-80 years using data on one-year cohort age-specific death rates from the Human Mortality Database (HMD). Totally, data for 2,294 cohorts of men and women from 76 populations were analyzed. Changes of the Gompertz slope parameter in the studied cohorts revealed two distinct patterns for actuarial aging rate. In higher mortality Eastern European countries actuarial aging rates showed continuous decline from the 1910 to 1940 birth cohort. In lower mortality Western European countries, Australia, Canada, Japan, New Zealand, and USA actuarial aging rates declined from the 1910th to approximately 1930th cohort and then increased. Overall, in 50 out of 76 populations (68%) actuarial aging rate demonstrated decreasing pattern of change over time. Compensation effect of mortality (CEM) was tested for the first time in human cohorts and the cohort species-specific lifespan was estimated. CEM was confirmed using cohort data and human cohort species-specific lifespan estimates were similar to the estimates obtained for the cross-sectional data published earlier.

Biomarkers of aging - current state of knowledge.

Aging is a process of gradual decline in the functional capacity of the human body that leads to a significant increase in the risk of death over time. Although it is a process universal to all animals, its rate is not the same. Biomarkers of aging aim to better describe the aging process at the level of the individual, organ, tissue, or single cell. They are used to estimate the rate of aging and predict the probability of death. They are good indication of the current state of the organism and are more accurate in predicting a person's susceptibility to disease, its progression and the likelihood of complications and death. Simple biomarkers measure only one parameter or a narrow group of related parameters that have a known association with age, in human or in a laboratory model. They can be divided into molecular (based on features of aging), functional (describing decreasing functional capacity during aging) and anthropometric (describing structural changes). Composite biomarkers are the most comprehensive way of measuring biological age. They combine a large amount of data, which they evaluate using algorithms often based on artificial intelligence. The most widely used method for measuring biological age in composite biomarkers is the epigenetic clock. The aim of this article is to review the many existing markers of aging and describe their relationship to aging.

An underappreciated peculiarity of late-life human mortality kinetics assessed through the lens of a generalization of the Gompertz-Makeham law.

Much attention in biogerontology is paid to the deceleration of mortality rate increase with age by the end of a species-specific lifespan, e.g. after ca. 90 years in humans. Being analyzed based on the Gompertz law µ(t)=µ0e^γt with its inbuilt linearity of the dependency of lnµ on t, this is commonly assumed to reflect the heterogeneity of populations where the frailer subjects die out earlier thus increasing the proportions of those whose dying out is slower and leading to decreases in the demographic rates of aging. Using Human Mortality Database data related to France, Sweden and Japan in five periods 1920, 1950, 1980, 2018 and 2020 and to the cohorts born in 1920, it is shown by LOESS smoothing of the lnµ-vs-t plots and constructing the first derivatives of the results that the late-life deceleration of the life-table aging rate (LAR) is preceded by an acceleration. It starts at about 65 years and makes LAR at about 85 years to become 30% higher than it was before the acceleration. Thereafter, LAR decreases and reaches the pre-acceleration level at ca. 90 years. This peculiarity cannot be explained by the predominant dying out of frailer subjects at earlier ages. Its plausible explanation may be the acceleration of the biological aging in humans at ages above 65-70 years, which conspicuously coincide with retirement. The decelerated biological aging may therefore contribute to the subsequent late-life LAR deceleration. The biological implications of these findings are discussed in terms of a generalized Gompertz-Makeham law µ(t) = C(t)+µ0e^f(t).

Aging varies greatly within a single genus: A demographic study of Rhododendron spp. in botanic gardens.

PREMISE: There is mounting evidence that age matters in plant demography, but also indications that relationships between age and demographic rates may vary significantly among species. Age-based plant demographic data, however, are time-consuming to collect and still lacking for most species, and little is known about general patterns across species or what may drive differences. METHODS: We used individual birth and death records for 12 Rhododendron species from botanic gardens and conducted Bayesian survival trajectory analyses to assess how mortality changed with age. We calculated the demographic measures of aging rate, life-span equality, and life expectancy for each species, and assessed their relationships with the climatic conditions at species' sites of ancestral origin and with taxonomic group (subgenus). RESULTS: We found substantial among-species variation in survival trajectories, with mortality increasing, decreasing, or remaining constant with advancing age. Moreover, we found no relationships between demographic measures and ancestral climatic conditions but there were statistically significant differences among taxonomic groups in the rate of change in mortality with age (aging rate). CONCLUSIONS: We conclude that demographic consequences of aging can differ qualitatively, even among species in the same genus. In addition, taxonomic trends in aging rates indicate they may be genetically determined, though evolutionary drivers are still unclear. Furthermore, we suggest there is untapped potential in using botanic garden records in future studies on plant life history.

Aging rate, environmental risk and production efficiency of the low-density polyethylene (LDPE) films with contrasting thickness in irrigated region.

Physical thickness of low-density polyethylene (LDPE) films might determine the release rate of phthalic acid esters (PAEs) & structural integrity and affect production efficiency. However, this critical issue is still unclear and little reported. Aging effects were evaluated in LDPE films with the thickness of 0.006, 0.008, 0.010 and 0.015 mm in a maize field of irrigation region. The Scanning electron microscope (SEM) results showed that the proportion of damaged area (Dam) to total area of LDPE films was massively lowered with increasing thickness after aging. The highest and lowest Dam was 32.2% and 3.5% in 0.006 and 0.015 mm films respectively. Also, the variations in peak intensity of asymmetric & symmetrical stretching vibrations (ASVI & SSVI) were detected using Fourier transform infrared spectrum (FTIR), indicating that the declines in peak intensity tended to be slower with thickness. Interestingly, the declines in physical integrity were tightly associated with increasing exhalation rate of PAEs. Average releasing rate of PAEs was 38.2%, 31.4%, 31.5% and 19.7% in LDPE films from 0.006 to 0.015 mm respectively. Critically, thicker film mulching can lead to greater soil water storage at plough layer (SWS-PL) and better thermal status, accordingly harvesting higher economic benefit. Therefore, LDPE film thickening may be a solution to reduce environmental risk but improve production efficiency in arid region.

On the Commentary by Anatoly I. Mikhalsky Published in Biochemistry (Moscow), Vol. 88, No. 1, pp. 162-163 (2023).

Caution is needed in using cohort data when studying age-related mortality dynamics, because mortality depends not only on age, but also on the changing living conditions over time. A hypothesis is proposed for further testing that the actuarial aging rate may even decrease in more recent birth cohorts of people due to improved living conditions.

On the Paper by Leonid A. Gavrilov and Natalia S. Gavrilova entitled "Trends in Human Species-Specific Lifespan and Actuarial Aging Rate" Published in Biochemistry (Moscow), Vol. 87, Nos. 12-13, pp. 1622-1633 (2022).

The methodology used for analyzing the survival process should keep in mind heterogeneity in empirical data. Cross-sectional data are more heterogeneous in comparison with birth-cohort data.

Mitochondrial ROS production, oxidative stress and aging within and between species: Evidences and recent advances on this aging effector.

Mitochondria play a wide diversity of roles in cell physiology and have a key functional implication in cell bioenergetics and biology of free radicals. As the main cellular source of oxygen radicals, mitochondria have been postulated as the mediators of the cellular decline associated with the biological aging. Recent evidences have shown that mitochondrial free radical production is a highly regulated mechanism contributing to the biological determination of longevity which is species-specific. This mitochondrial free radical generation rate induces a diversity of adaptive responses and derived molecular damage to cell components, highlighting mitochondrial DNA damage, with biological consequences that influence the rate of aging of a given animal species. In this review, we explore the idea that mitochondria play a fundamental role in the determination of animal longevity. Once the basic mechanisms are discerned, molecular approaches to counter aging may be designed and developed to prevent or reverse functional decline, and to modify longevity.

Sex-and Age-Based Etiological Analysis of 2901 Patients With Dysphonia in a Japanese Tertiary Medical Institute.

OBJECTIVES: Societal aging is a grave concern in Japan, and its impact on voice clinics has not been investigated. This study aimed to clarify recent demographic features of geriatric dysphonia at a tertiary medical institute in Japan. STUDY DESIGN: Retrospective study. METHODS: The medical records of 2901 patients newly referred to the Voice Outpatient Clinic of the University of Tokyo Hospital between 2003 and 2020 were analyzed for age, sex, and etiology. RESULTS: The mean ± standard deviation age of all patients was 53.2 ± 20.7 (median, 58; range, 0-95) years. The aging rate (ratio of patients aged ≥65 years) increased continuously during the study period, and the recent aging rate was the highest in the world (43%). However, its rate of increase has slowed over the past 10 years. The etiologies of dysphonia associated with the largest number of older patients were vocal fold immobility (32%), vocal fold atrophy (23%), and benign vocal fold lesions (11%). The highest aging rate was detected in patients with laryngeal cancer/leukoplakia, vocal tremor, vocal fold atrophy, sulcus vocalis, and vocal fold immobility. CONCLUSIONS: Societal aging substantially increased the aging rate of patients with dysphonia in a Japanese voice clinic. The incidence of vocal fold immobility and atrophy is expected to continue to increase, whereas that of benign vocal fold lesions is expected to decrease.

Trends in Human Species-Specific Lifespan and Actuarial Aging Rate.

The compensation effect of mortality (CEM) was tested and species-specific lifespan was estimated using data on one-year age-specific death rates from the Human Mortality Database (HMD). CEM was confirmed using this source of the data and human species-specific lifespan estimates were obtained, which were similar to the estimates published before. Three models (Gompertz-Makeham, Gompertz-Makeham with mean-centered age, and Gompertz) produced similar estimates of the species-specific lifespan. These estimates demonstrated some increase over time. Attempts to measure aging rates through the Gompertz slope parameter led to the conclusion that actuarial aging rates were stable during most of the 20th century, but recently demonstrated an increase over time in the majority (74%) of studied populations. This recent phenomenon is most likely caused by more rapid historical decline of mortality at the younger adult age groups compared to the older age groups, thus making the age gradient in mortality steeper over time. There is no biomedical reason to believe that human aging rates accelerated recently, so that the actuarial aging rate is probably not a good measure of true aging rate (rate of functional loss). Therefore, better measures of aging rate need to be developed.

Predicting physiological aging rates from a range of quantitative traits using machine learning.

It is widely thought that individuals age at different rates. A method that measures "physiological age" or physiological aging rate independent of chronological age could therefore help elucidate mechanisms of aging and inform an individual's risk of morbidity and mortality. Here we present machine learning frameworks for inferring individual physiological age from a broad range of biochemical and physiological traits including blood phenotypes (e.g., high-density lipoprotein), cardiovascular functions (e.g., pulse wave velocity) and psychological traits (e.g., neuroticism) as main groups in two population cohorts SardiNIA (~6,100 participants) and InCHIANTI (~1,400 participants). The inferred physiological age was highly correlated with chronological age (R2 > 0.8). We further defined an individual's physiological aging rate (PAR) as the ratio of the predicted physiological age to the chronological age. Notably, PAR was a significant predictor of survival, indicating an effect of aging rate on mortality. Our trait-based PAR was correlated with DNA methylation-based epigenetic aging score (r = 0.6), suggesting that both scores capture a common aging process. PAR was also substantially heritable (h2~0.3), and a subsequent genome-wide association study of PAR identified significant associations with two genetic loci, one of which is implicated in telomerase activity. Our findings support PAR as a proxy for an underlying whole-body aging mechanism. PAR may thus be useful to evaluate the efficacy of treatments that target aging-related deficits and controllable epidemiological factors.

Effect of longevity genetic variants on the molecular aging rate.

We conducted a genome-wide association study of 1320 centenarians from the New England Centenarian Study (median age = 104 years) and 2899 unrelated controls using >9 M genetic variants imputed to the HRC panel of ~65,000 haplotypes. The genetic variants with the most significant associations were correlated to 4131 proteins that were profiled in the serum of a subset of 224 study participants using a SOMAscan array. The genetic associations were replicated in a genome-wide association study of 480 centenarians and ~800 controls of Ashkenazi Jewish descent. The proteomic associations were replicated in a proteomic scan of approximately 1000 Ashkenazi Jewish participants from a third cohort. The analysis replicated a protein signature associated with APOE genotypes and confirmed strong overexpression of BIRC2 (p < 5E-16) and under-expression of APOB in carriers of the APOE2 allele (p < 0.05). The analysis also discovered and replicated associations between longevity variants and slower changes of protein biomarkers of aging, including a novel protein signature of rs2184061 (CDKN2A/CDKN2B in chromosome 9) that suggests a genetic regulation of GDF15. The analyses showed that longevity variants correlate with proteome signatures that could be manipulated to discover healthy-aging targets.

Assessing the rate of aging to monitor aging itself.

Healthy aging is the prime goal of aging research and interventions. Healthy aging or not can be quantified by biological aging rates estimated by aging clocks. Generation and accumulation of large scale high-dimensional biological data together with maturation of artificial intelligence among other machine learning techniques, have enabled and spurred the rapid development of various aging rate estimators (aging clocks). Here we review the data sources and compare the algorithms of recent human aging clocks, and the applications of these clocks in both researches and daily life. We envision that not only more and multiscale data on cross-sectional data will add momentum to the aging clock development, new longitudinal and interventional data will further raise the aging clock development to the next level to be trained by true biological age such as morbidity and mortality age.

Aging of exogenous arsenic in flooded paddy soils: Characteristics and predictive models.

Understanding the arsenic (As) aging process is important for predicting the environmental behavior of exogenous As in paddy soils. In this work, samples of sixteen paddy soils with various soil properties were spiked with two concentrations (30 and 100 mg kg-1) of arsenate and subjected to a 360 day-long incubation under continuous flooding condition. Soil available As extracted by 0.05 M NH4H2PO4 was monitored through the aging process. Results showed that the available As%, the percentage of remaining available As in aged soils to added total As, fell from 44.2% to 41.9% on the 1st day to 22.0% and 23.0% on the 115th day for the low and high As spiked soils, respectively, then it remained basically unchanged after the 115th day. The pseudo-second order equation could adequately describe the aging kinetics of exogenous As in paddy soils. There was no significant difference in As aging parameters between the two spiked concentrations. Contents of soil free Al and Mn oxides, clay and cation exchange capacity strongly affected the aging rate of exogenous As. An empirical model, incorporating soil pH, cation exchange capacity, Olsen-P and flooding time, was developed to predict well the change of soil available As% during aging process (R2 = 0.711). The model could be potentially utilized to manage As-contaminated paddy fields and normalize ecotoxicity and bioaccumulation datasets in attempt to derive more widely applicable soil environmental quality criteria for As.

Decrease in Human Aging Rate Since the Middle of the 20th Century.

The plot of the mortality rate minus the constant A of the Gompertz-Makeham equation and the plot of the mortality intensity increment d(m) reflect the actual rate of biological aging. It was shown that since the middle of the 20th century there has been a slowdown in aging for all the countries of the world that were studied (for available periods in the history), in all parameters: R0 and k coefficients of the Gompertz equation, mortality intensity increment d(m) and maximum life span. The slowdown in the aging rate of continues to the present. The probable cause is a significant improvement in medical and social care and quality of life since the mid-20th century and the possible influence of the therapy of chronic diseases on the aging processes.

Developmental Tuning of Epigenetic Clock.

Research in the field of gerontology has traditionally focused on later life stages. There is increasing evidence, however, that both the rate of age-related functional decline and the later-life health status can be programmed during early development. The central role of epigenetic mechanisms (methylation of DNA, histone modifications and regulation by non-coding RNAs) in mediating these long-term effects has been elucidated. Both rate and direction of age-associated change of epigenetic patterns ("epigenetic drift") were shown to be largely dependent on early-life environmental conditions. Inter-individual divergences in epigenetic profiles may arise following the stochastic errors in maintaining epigenetic marks, but they may also be adaptively mediated by specific environmental cues. Recent cohort studies indicate that ticking rate of epigenetic clock, estimated by a DNA methylation-based methods, may be developmentally adjusted, and that individual's discrepancies among epigenetic and chronological age would be likely programmed early in development. In this Perspective article, recent findings suggesting the importance of early-life determinants for life-course dynamics of epigenetic drift are summarized and discussed.

[anthropometric indices of women of the Yakut nationality (from 18 to 89 years) depending on the variant speed of aging].

OBJECTIVE: Introduction: the paper deals with the biological age of women living in extreme climatogeographic conditions of the Republic of Sakha (Yakutia). The aim of the study was to identify the anthropometric characteristics of women of yakut nationality (from 18 to 89 years), depending on the rate of aging. PATIENTS AND METHODS: Materials and methods: Anthropometric measurements were carried out by the classical method of V. V. Bunak. The absolute values of the main body components (fat, muscle and bone mass) were calculated using the Matiegka formulas. Body mass index (BMI) was determined. The variant of the rate of aging was revealed by the value of the rate of aging coefficient (Gorelkin A. G., Pinkhasov B. B., 2010). The obtained material was processed using the methods of parametric and nonparametric statistics of SPSS 17.0 application package. RESULTS: Results: The age characteristics of the distribution of the rate of aging women of Yakutia are revealed. The predominant option of ageing among young women, the first and second periods of adulthood was the normal rate of ageing, and among older women and senile women was the slow option of ageing. The share of accelerated aging is significantly reduced in older age groups until complete disappearance in the elderly age group. Women with accelerated aging had significantly greater body weight, relative weight of fat component than women with other options of aging rate. In terms of BMI, women with accelerated aging were significantly more likely to be overweight and obese. CONCLUSION: Conclusions: Biological age women of Yakutia has the age features. Ethno-territorial features of distribution of variants of aging rate of women living in different regions of Russia are established. The obtained results can be one of the biomarkers for determining the rate of aging of the female body, and used to develop recommendations for improving the quality and increasing the life expectancy of the female population of the Republic of Sakha (Yakutia).