Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial.

The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan1-3. Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients4, results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm)5-7, and is established to increase healthy lifespan in multiple species8,9. Here we report the results of a post hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 yr (ref. 10). We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by various DNAm clocks including PhenoAge and GrimAge. Treatment effect sizes were small. Nevertheless, modest slowing of the pace of aging can have profound effects on population health11-13. The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies14-16 and contrasting with reports that biological aging may not be modifiable17. Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality18-20.

Biological aging in maltreated children followed up into middle adulthood.

BACKGROUND: Childhood adversity has been linked to many indicators of shorter healthy lifespan, including earlier onset of disease and disability as well as early mortality. These observations suggest the hypothesis that childhood maltreatment may accelerate aging. OBJECTIVE: To characterize the relationship between childhood maltreatment and accelerated biological aging in a prospective cohort of 357 individuals with documented cases of childhood maltreatment and 250 controls matched on demographic and socioeconomic factors. METHODS: Cases were drawn from juvenile and adult court records from the years 1967 through 1971 in a large Midwest metropolitan geographic area. Cases were defined as having court-substantiated cases of childhood physical or sexual abuse, or neglect occurring at age 11 or younger. Controls were selected from the same schools and hospitals of birth and matched on age, sex, race, and approximate socioeconomic status. We compared biological aging in these two groups using two blood-chemistry algorithms, the Klemera-Doubal method Biological Age (KDM BA) and the PhenoAge. Algorithms were developed and validated in data from the National Health and Nutrition Examination Surveys (NHANES) using published methods and publicly available software. RESULTS: Participants (55% women, 49% non-White) had mean age of 41 years (SD=4). Those with court substantiated childhood maltreatment history exhibited more advanced biological aging as compared with matched controls, although this difference was statistically different for only the KDM BA measure (KDM BA Cohen's D=0.20, 95% CI=[0.03,0.36], p = 0.02; PhenoAge Cohen's D=0.09 95% CI=[-0.08,0.25], p = 0.296). In subgroup analyses, maltreatment effect sizes were larger for women as compared to men and for White participants as compared to non-White participants, although these differences were not statistically significant at the α= 0.05 level. CONCLUSIONS AND RELEVANCE: As of midlife, effects of childhood maltreatment on biological aging are small in magnitude but discernible. Interventions to treat psychological and behavioral sequelae of exposure to childhood maltreatment, including in midlife adults, have potential to protect survivors from excess burden of disease, disability, and mortality in later life.

Sulfated glycoprotein-1 (SGP-1) expression in ovine endometrium during the oestrous cycle and early pregnancy.

This study determined effects of day of oestrous cycle and early pregnancy on sulfated glycoprotein-1 (SGP-1) expression in ovine endometrium. A 364-bp clone of the ovine SGP-1 mRNA was amplified from reverse transcribed Day-15 cyclic endometrial mRNA using the polymerase chain reaction (PCR) and primers specific for the rat SGP-1 mRNA sequence. Nucleotide sequence of the ovine SGP-1 cDNA shared significant identity with rat SGP-1 and human prosaposin. Ewes (n = 40) were hysterectomized on either Day 1, 6, 11, 13 or 15 of the oestrous cycle or on Day 11, 13, 15, 17 or 25 of early pregnancy. Total cellular RNA was isolated from endometrium and subjected to Northern and slot blot hybridization analyses using an antisense cRNA probe transcribed from the ovine SGP-1 cDNA clone. A single 2.6-kb mRNA transcript was detected by Northern hybridization analyses. Slot blot hybridization analyses indicated that steady-state levels of endometrial SGP-1 mRNA varied during the oestrous cycle (cubic, P < 0.02) and increased between Day 11 and Day 25 of early pregnancy (linear, P < 0.01). On Days 11, 13 and 15, endometrial SGP-1 mRNA levels were greater in pregnant ewes than in cyclic ewes (day x pregnancy status, P < 0.01). Immunohistochemical localization of SGP-1 in uterine tissues with rabbit anti-rat SGP-1 antibody revealed intense immunoreactivity associated primarily with the endometrial epithelium. These results indicate that the ovine endometrium expresses SGP-1, a prosaposin, and that SGP-1 expression varies during the oestrous cycle and is enhanced by the conceptus. The presence of SGP-1 in the endometrium suggests intracellular and extracellular roles for this protein in glycosphingolipid metabolism or transport in the uterine environment.