DHT and estradiol correlate to slowdown of biological aging

Nelson Vergel

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Endocrine Society's 98th Annual Meeting and Expo, April 1–4, 2016 - Boston

SAT-152:
Sex Hormones and Biological Ageing: Results of Epidemiological and Mendelian Randomisation Studies of the Bioactive Metabolites of Testosterone, Dihydrotestosterone and Estradiol, and Leucocyte Telomere Length in Community-Dwelling Men


Bu Beng Yeap1, Matthew W Knuiman1, Mark L Divitini1, Jennie Hui2, Gillian M Arscott2, David J Handelsman3, Susan McLennan4, Stephen M. Twigg4, Brendan McQuillan1, Joseph Hung1 and John P Beilby2

1University of Western Australia, Perth, Australia
2Sir Charles Gairdner Hospital, Perth, Australia
3ANZAC Research Institute, University of Sydney, Sydney, Australia
4University of Sydney, Sydney, Australia

Presentation Number: SAT-152
Date of Presentation: April 2, 2016


ABSTRACT
Abstract:

Context
Advancing age is accompanied by accumulation of ill-health and by shortening of chromosomal telomeres signifying biological ageing. The male sex hormone testosterone (T) is metabolised to dihydrotestosterone (DHT) by the 5α-reductase gene (SRD5A2) and to estradiol (E2) by the aromatase gene (CYP19A1). Telomere length is preserved by the enzyme telomerase, and T and E2 regulate telomerase expression and activity in vitro. However, the effect of sex hormones on telomere length in vivo is unclear.


Objectives
To establish whether circulating T or its metabolites DHT or E2, and single nucleotide polymorphisms (snps) in SRD5A2 or CYP19A1 associate with leucocyte telomere length (LTL) in men.

Participants and methods
Early morning serum T, DHT and E2 were assayed using mass spectrometry, and SRD5A2 and CYP19A1 snps and LTL analysed by PCR in 980 community-dwelling men from the Western Australian Busselton Health Survey. LTL was expressed as the T/S ratio. Age-adjusted correlations of T, DHT and E2 with LTL were assessed. Mendelian randomisation analyses of functional SRD5A2 and CYP19A1 snps with the outcome of LTL were performed, adjusting for age and other covariates.

Results
Men were aged (mean±SD) 53.7±15.6 years. LTL decreased linearly with age, from T/S ratio 1.89±0.41 at <30 years to 1.50±0.49 at 70 to <80 years (r=-0.225, p<0.0001). After adjustment for age, DHT and E2 were positively correlated with LTL (DHT r=0.069, p=0.030; E2 r=0.068, p=0.034). The SRD5A2 rs9282858 snp was associated with lower serum DHT (GA vs GG 1.41 vs 1.62 nmol/L, p=0.016) but not with LTL (1.54 vs 1.57, p=0.069). Three dominant alleles of CYP19A1 were each associated with both lower serum E2 and shorter LTL: rs2899470 GT+TT vs GG (E2 59.3 vs 68.6 pmol/L, p<0.0001; T/S ratio 1.54 vs 1.62, p=0.045), rs10046 CT+CC vs TT (60.5 vs 68.1 pmol/L, p=0.0005, 1.54 vs 1.62, p=0.035) and rs700518 GA+AA vs GG (59.9 vs 68.9 pmol/L, p<0.0001, 1.54 vs 1.63, p=0.020).

Conclusions
In men, serum DHT and E2 correlate with LTL independently of age. Aromatase gene polymorphisms include 3 dominant alleles which are associated with both lower serum E2 (approximately 10 pmol/L) and shorter LTL (T/S ratio 0.08). Thus in Mendelian randomisation analysis inferring causality, modestly reduced serum E2 corresponds to a difference in LTL approximating an increase of a decade of age. E2 influences telomere length in vivo thus providing a rationale for randomised placebo-controlled trials to examine whether T via its metabolism to E2 might slow biological ageing in men.


- See more at: http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2016.RE.11.SAT-152#sthash.BTqiKznX.dpuf
 
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