News in Brief
Authors: Hannah Linne
Journal: The Lancet Healthy Longevity (2021)

Total daily energy expenditure (total expenditure) is an important determinant of human development, health, and physiology; however, little is known about how or why total expenditure changes over the human lifespan. In a large study of 6421 individuals (aged 8 days to 95 years) from 29 countries, Herman Pontzer (Duke University, Durham, NC, USA) and colleagues used a database of doubly labelled water measurements to investigate the effects of age, body composition, and sex on total expenditure. Total expenditure in all individuals was calculated using a single validated equation, with basal expenditure (ie, the metabolic rate at rest) measured by indirect calorimetry. Total and basal expenditure increased with fat-free mass in a power-law manner, necessitating the calculation of size-adjusted energy expenditures. Segmented regression analyses revealed four distinct phases of total and basal expenditure: (1) in neonates, both total and basal expenditure increased rapidly after age 1 month, reaching levels approximately 50% higher than those observed in adults by age 9–15 months; (2) in juveniles, total and basal expenditure declined from age 1 year to reach adult levels by age 20·5 years, with sex having no effect on the rate of decline; (3) in adults, total and basal expenditure remained stable (regardless of sex) from age 20 to 60 years, even during pregnancy; and (4) in older adults, total and basal expenditure declined from around 60 years of age, reaching approximately 26% lower levels than those of middle-aged adults at around 90 years. These findings could help inform targeted nutrition and health strategies over the life-course. Reproductive lifespan affects fertility and women's health; however, the molecular processes underlying reproductive longevity and the timing of reproductive senescence (age at natural menopause [ANM]), and how they can be manipulated to preserve fertility, are unclear. Using genome-wide array data from 201 323 women of European ancestry, Katherine S Ruth (University of Exeter, Exeter, UK) and colleagues identified 290 significant independent signals associated with ANM (p<5 × 10−8). The identified loci were involved in mediating a range of DNA damage response (DDR) pathways and apoptosis, with 81 of the 290 signals (91 genes) predicted to be deleterious for gene function. Women carrying loss of function (LOF) variants in BRCA2 reported ANM 1·54 years (95% CI 0·73–2·34; p<6·8 × 10−5) earlier and those carrying LOF variants in CHEK2 3·49 years (2·36–4·63; p<1 × 10−13) later than non-carriers. In vivo, two identified genes (Dmc1 and Brsk1) were differentially expressed in the ovaries of offspring from obese mice, which have a reduced ovarian reserve, suggesting that maternal exposures could affect the reproductive lifespan of their offspring in-utero. Modulation of DDR genes (Chek1 and Chek2) in mice preserved or increased the ovarian reserve and improved ovarian function, highlighting potential therapeutic targets. Causal inference analyses indicated that delays in ANM increased the relative risks of several hormone-sensitive cancers by up to 5%, but increased bone mineral density and decreased fracture risk and risk of type 2 diabetes Unlike previous observational studies, no causal associations between ANM and cardiovascular disease, lipid levels, Alzheimer's disease, body mass, or longevity were observed. People with diabetes have an increased risk of developing Alzheimer's disease, the most common form of dementia. In a retrospective study of 282 people (mean age 76 years) with Alzheimer's disease-related cognitive impairment (ADCI), Seong Ho Heong (Yonsei University College of Medicine, Seoul, South Korea) and colleagues investigated the association between use of dipeptidyl peptidase-4 (DPP-4) inhibitors, an oral antidiabetic medication, and amyloid aggregation and cognitive decline. People with preclinical, early, or probable Alzheimer's disease and positive 18F-florbetaben amyloid PET images were divided into three groups: people with diabetes on DPP-4 inhibitors (n=70), people with diabetes not on DPP-4 inhibitors (n=71), and those without diabetes (n=141), who were matched for age, sex, and education levels. Global and regional amyloid retention and longitudinal changes in cognition (assessed with the Mini-Mental State Examination [MMSE]), were analysed, with all patients followed up for up to 5 years. After adjusting for age, sex, education, cognitive status, and APOE ε4 carrier status, individuals with diabetes on DPP-4 inhibitors had a lower global amyloid burden than those not on DPP-4 inhibitors (β=0·075 [SE 0·024]; p=0·002) and individuals without diabetes (β=0·054 [0·021]; p=0·010). Similar patterns were observed with the amyloid burden in temporo-parietal regions. After adjusting for factors that could affect MMSE scores, the scores of people with diabetes on DPP-4 inhibitors declined 0·77 points per year more slowly than those not on DPP-4 inhibitors. Further research is needed to understand whether DPP-4 inhibitors might benefit patients with Alzheimer's disease.