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Changes in daily energy Uncovering the molecular Alzheimer’s disease-related For Herman Pontzer and
expenditure throughout the processes of reproductive cognitive impairment colleagues’ study see
https://science.sciencemag.org/
human life-course ageing in women People with diabetes have an increased
For Katherine S Ruth and
Total daily energy expenditure Reproductive lifespan affects fertility risk of developing Alzheimer’s colleagues’ study see
(total expenditure) is an important and women’s health; however, the disease, the most common form of 2021; 596: 393–97
determinant of human development, molecular processes underlying dementia. In a retrospective study For Seong Ho Heong and
health, and physiology; however, reproductive longevity and the timing of 282 people (mean age 76 years) colleagues’ study see
https://doi.org/10.1212/
little is known about how or why of reproductive senescence (age at with Alzheimer’s disease-related WNL.0000000000012534
total expenditure changes over the natural menopause [ANM]), and how cognitive impairment (ADCI), Seong
human lifespan. In a large study of they can be manipulated to preserve Ho Heong (Yonsei University College
6421 individuals (aged 8 days to fertility, are unclear. Using genome- of Medicine, Seoul, South Korea) and
95 years) from 29 countries, Herman wide array data from 201 323 women colleagues investigated the association
Pontzer (Duke University, Durham, of European ancestry, Katherine S Ruth between use of dipeptidyl peptidase-4
NC, USA) and colleagues used a (University of Exeter, Exeter, UK) and (DPP-4) inhibitors, an oral antidiabetic
database of doubly labelled water colleagues identified 290 significant medication, and amyloid aggregation
measurements to investigate the independent signals associated with and cognitive decline. People
effects of age, body composition, ANM (p<5 × 10–⁸). The identified loci with preclinical, early, or probable
and sex on total expenditure. Total were involved in mediating a range Alzheimer’s disease and positive
expenditure in all individuals was of DNA damage response (DDR) ¹⁸F-florbetaben amyloid PET images
calculated using a single validated pathways and apoptosis, with 81 of were divided into three groups: people
equation, with basal expenditure the 290 signals (91 genes) predicted with diabetes on DPP-4 inhibitors
(ie, the metabolic rate at rest) to be deleterious for gene function. (n=70), people with diabetes not on
measured by indirect calorimetry. Women carrying loss of function DPP-4 inhibitors (n=71), and those
Total and basal expenditure (LOF) variants in BRCA2 reported without diabetes (n=141), who were
increased with fat-free mass in a ANM 1·54 years (95% CI 0·73–2·34; matched for age, sex, and education
power-law manner, necessitating p<6·8 × 10 –⁵) earlier and those levels. Global and regional amyloid
the calculation of size-adjusted carrying LOF variants in CHEK2 3·49 retention and longitudinal changes
energy expenditures. Segmented years (2·36–4·63; p<1 × 10–¹³) later in cognition (assessed with the Mini-
regression analyses revealed four than non-carriers. In vivo, two Mental State Examination [MMSE]),
distinct phases of total and basal identified genes (Dmc1 and Brsk1) were analysed, with all patients
expenditure: (1) in neonates, both were differentially expressed in the followed up for up to 5 years. After
total and basal expenditure increased ovaries of offspring from obese mice, adjusting for age, sex, education,
rapidly after age 1 month, reaching which have a reduced ovarian reserve, cognitive status, and APOE ε4 carrier
levels approximately 50% higher suggesting that maternal exposures status, individuals with diabetes on
than those observed in adults by age could affect the reproductive lifespan DPP-4 inhibitors had a lower global
9–15 months; (2) in juveniles, total of their offspring in-utero. Modulation amyloid burden than those not on
and basal expenditure declined from of DDR genes (Chek1 and Chek2) DPP-4 inhibitors (β=0·075 [SE 0·024];
age 1 year to reach adult levels by in mice preserved or increased the p=0·002) and individuals without
age 20·5 years, with sex having no ovarian reserve and improved ovarian diabetes (β=0·054 [0·021]; p=0·010).
effect on the rate of decline; (3) in function, highlighting potential Similar patterns were observed with the
adults, total and basal expenditure therapeutic targets. Causal inference amyloid burden in temporo-parietal
remained stable (regardless of analyses indicated that delays in ANM regions. After adjusting for factors that
sex) from age 20 to 60 years, even increased the relative risks of several could affect MMSE scores, the scores
during pregnancy; and (4) in older hormone-sensitive cancers by up of people with diabetes on DPP-4
adults, total and basal expenditure to 5%, but increased bone mineral inhibitors declined 0·77 points per year
declined from around 60 years of density and decreased fracture risk more slowly than those not on DPP-4
age, reaching approximately 26% and risk of type 2 diabetes Unlike inhibitors. Further research is needed to
lower levels than those of middle- previous observational studies, no understand whether DPP-4 inhibitors
aged adults at around 90 years. These causal associations between ANM and might benefit patients with Alzheimer’s
findings could help inform targeted cardiovascular disease, lipid levels, disease.
nutrition and health strategies over Alzheimer’s disease, body mass, or
the life-course. longevity were observed. Hannah Linne
www.thelancet.com/healthy-longevity Vol 2 September 2021 e543

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