Biological aging is the gradual, progressive decline in system integrity that occurs with advancing chronological age, causing morbidity and disability. Measurements of the pace of aging are needed as surrogate endpoints in trials of therapies designed to prevent disease by slowing biological aging. We report a blood-DNA-methylation measure that is sensitive to variation in pace of biological aging among individuals born the same year. We first modeled change-over-time in 18 biomarkers tracking organ-system integrity across 12 years of follow-up in n = 954 members of the Dunedin Study born in 1972–1973. Rates of change in each biomarker over ages 26–38 years were composited to form a measure of aging-related decline, termed Pace-of-Aging. Elastic-net regression was used to develop a DNA-methylation predictor of Pace-of-Aging, called DunedinPoAm for Dunedin(P)ace(o)f(A)ging(m)ethylation. Validation analysis in cohort studies and the CALERIE trial provide proof-of-principle for DunedinPoAm as a single-time-point measure of a person’s pace of biological aging.

The practice of diagnosing mental disorders is at a crossroads. The Diagnostic and Statistical Manual of Mental Disorders, which guides diagnostic practice, is being questioned.¹ The US National Institute of Mental Health has called for a new approach to studying mental disorders,² and the public is confused about what constitutes a mental disorder, resulting in a practice known as diagnosis shopping.³ Our thesis is that progress in conceptualizing mental disorders has been delayed by the field’s limiting focus on cross-sectional information. This study demonstrates how much novel information can be learned by taking a longitudinal, life-course view of mental disorders.

Systemic chronic inflammation (SCI) is persistent, health-damaging, low-grade inflammation that plays a major role in immunosenescence and in development and progression of many diseases. But currently, there are no recognized standard biomarkers to assess SCI levels alone, and SCI is typically measured by combining biomarkers of acute inflammation and infection, e.g., CRP, IL-6, and TNFα. In this review, we highlight 10 properties and characteristics that are shared by the blood protein soluble urokinase plasminogen activator receptor (suPAR) and SCI, supporting the argument that suPAR is a biomarker of SCI: (1) Expression and release of suPAR is upregulated by immune activation; (2) uPAR and suPAR exert pro-inflammatory functions; (3) suPAR is associated with the amount of circulating immune cells; (4) Blood suPAR levels correlate with the levels of established inflammatory biomarkers; (5) suPAR is minimally affected by acute changes and short-term influences, in contrast to many currently used markers of systemic inflammation; (6) Like SCI, suPAR is non-specifically associated with multiple diseases; (7) suPAR and SCI both predict morbidity and mortality; (8) suPAR and SCI share the same risk factors; (9) suPAR is associated with risk factors and outcomes of inflammation above and beyond other inflammatory biomarkers; (10) The suPAR level can be reduced by anti-inflammatory interventions and treatment of disease. Assessing SCI has the potential to inform risk for morbidity and mortality. Blood suPAR is a newer biomarker which may, in fact, be a biomarker of SCI since it is stably associated with inflammation and immune activation; shares the same risk factors as many age-related diseases; is both elevated by and predicts age-related diseases. There is strong evidence that suPAR is a prognostic marker of adverse events, morbidity, and mortality. It is associated with immune activity and prognosis across diverse conditions, including kidney disease, cardiovascular disease, cancer, diabetes, and inflammatory disorders. Thus, we think it likely represents a common underlying disease-process shared by many diseases; that is, SCI. We review the supporting literature and propose a research agenda that can help test the hypothesis that suPAR indexes SCI, with the potential of becoming the new gold standard for measuring SCI.

The ability to walk and gait speed depend on the function and interplay of the musculoskeletal, visual, central nervous, and peripheral nervous systems, as well as aerobic capacity, cardiorespiratory fitness, and energy production and delivery.^1,2 Reduced gait speed is a sign of advancing age³; it is associated with poorer response to rehabilitation, age-related diseases, including cardiovascular disease and dementia, and early mortality.^4-6

Exposure to adverse experiences, stress, and violence during childhood and adolescence is associated with elevated risk of physical and mental health problems in adulthood,¹ many of which have inflammatory origins. Inflammation could constitute one of the underlying mechanisms responsible for the biological embedding of childhood stress, indicating an association between exposure to early-life adversity and adverse health outcomes in later life.²

The plasma level of the inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) is a strong predictor of disease development and premature mortality in the general population. Unhealthy lifestyle habits such as smoking or unhealthy eating is known to elevate the suPAR level. We aimed to investigate whether change in lifestyle habits impact on the suPAR level, and whether the resultant levels are associated with mortality. Paired suPAR measurements from baseline- and the 5-year visit of the population-based Inter99 study were compared with the habits of diet, smoking, alcohol consumption, and physical activity. Paired suPAR measurements for 3225 individuals were analyzed by linear regression, adjusted for demographics and lifestyle habits. Compared to individuals with a healthy lifestyle, an unhealthy diet, low physical activity, and daily smoking were associated with a 5.9, 12.8, and 17.6% higher 5-year suPAR, respectively. During 6.1 years of follow-up after the 5-year visit, 1.6% of those with a low suPAR (mean 2.93 ng/ml) died compared with 3.8% of individuals with a high suPAR (mean 4.73 ng/ml), P < 0.001. In Cox regression analysis, adjusted for demographics and lifestyle, the hazard ratio for mortality per 5-year suPAR doubling was 2.03 (95% CI: 1.22–3.37). Lifestyle has a considerable impact on suPAR levels; the combination of unhealthy habits was associated with 44% higher 5-year suPAR values and the 5-year suPAR was a strong predictor of mortality. We propose suPAR as a candidate biomarker for lifestyle changes as well as the subsequent risk of mortality.