We read with interest a review by Deacon and Muir ('D&M') that concluded so-called 'non-therapeut... more We read with interest a review by Deacon and Muir ('D&M') that concluded so-called 'non-therapeutic' male circumcision (NTMC) of infants and children provides insufficient benefits and that risks were too high for it to be recommended in the UK [1]. Instead, they suggest delay until the boy is old enough to make his own decision. However, in contrast to the UK, policy statements by the American Academy of Pediatrics (AAP) [2] and Centers for Disease Control and Prevention (CDC) [3], finding benefits of NTMC exceed risks, are evidence-based. Flaws in D&M's arguments include reliance on small, weak, outof-date or inappropriate studies contradicted by more recent highquality evidence. Unlike systematic reviews and meta-analyses, D&M did not engage sufficiently with existing evidence. Studies cited were not rated by quality. They ignored a landmark high-quality study by CDC researchers of adverse events from 1.4 million neonatal and older age US males [4]. NTMC risk in infants was 0.4% and was 20-fold higher at age 1-9 and 10-fold higher at age ≥10. Similar values were cited in the AAP's policy statement. Thus D&M's claim of 1-5% risk may apply in non-US countries or to later circumcision. Also missing were key studies and important critiques of various publications they cited, as well as meta-analyses, and systematic reviews of benefits and risks (summarised in ref. [5]). If included, D&M's overall conclusion would have been more balanced. Instead of number-needed-to-treat (NNT) for each condition, they should have combined all such information into an overall risk-benefit analysis. An informed 'big picture' might then have emerged to better inform parents and practitioners. Several risk-benefit analyses have been published over the past decade, including ours in 'Mayo Clinic Proceedings' cited by the CDC. The only one for the UK found benefits exceeded risks by 200:1, with failure to perform NTMC in infancy likely resulting in at least one adverse medical condition among over half of uncircumcised males during their lifetime [6]. Contrary to D&M's assertion, the data we used for risk-benefit analyses were not 'over-estimates,' but came from high-quality studies. Contrary to their claim that the foreskin becomes fully retractile in 99% by age sixteen, our systematic review, involving 43 studies, included one finding full retractability was 51.1% in 1834 uncircumcised adolescent boys [7] and averaged 96.6% in men, being 92.2% in British National Servicemen [8].
Genetic variants of the kinase signaling gene MAP3K5 are associated with longevity. Here we explo... more Genetic variants of the kinase signaling gene MAP3K5 are associated with longevity. Here we explore whether the longevity-association involves protection against mortality in all individuals, or only in individuals with aging-related diseases. We tested the strongest longevity associated single nucleotide polymorphism (SNP), rs2076260, for association with mortality in 3,516 elderly American men of Japanese ancestry. At baseline (1991–1993), 2,461 had either diabetes (n=990), coronary heart disease (CHD; n=724), or hypertension (n=1,877), and 1,055 lacked any of these cardiometabolic diseases (CMDs). The men were followed from baseline until Dec 31, 2019. Longevity-associated genotype CC in a major allele homozygote model, and CC+TT in a heterozygote disadvantage model were associated with longer lifespan in individuals having a CMD (covariate-adjusted hazard ratio [HR] 1.23 [95% CI: 1.12–1.35, p=2.5x10–5] in major allele homozygote model, and 1.22 [95% CI: 1.11–1.33, p=1.10x10–5] i...
FOXO3 has been implicated in longevity in multiple populations. By DNA sequencing in long-lived i... more FOXO3 has been implicated in longevity in multiple populations. By DNA sequencing in long-lived individuals, we identified all single nucleotide polymorphisms (SNPs) in FOXO3 and showed 41 were associated with longevity. Thirteen of these had predicted alterations in transcription factor binding sites. Those SNPs appeared to be in physical contact, via RNA polymerase II binding chromatin looping, with sites in the FOXO3 promoter, and likely function together as a cis-regulatory unit. The SNPs exhibited a high degree of LD in the Asian population, in which they define a specific longevity haplotype that is relatively common. The haplotype was less frequent in whites and virtually nonexistent in Africans. We identified distant contact points between FOXO3 and 46 neighboring genes, through long-range physical contacts via CCCTC-binding factor zinc finger protein (CTCF) binding sites, over a 7.3 Mb distance on chromosome 6q21. When activated by cellular stress, we visualized movement of...
Objectives: To determine the relation between height, FOXO3 genotype and age of death in humans. ... more Objectives: To determine the relation between height, FOXO3 genotype and age of death in humans. Methods: Observational study of 8,003 American men of Japanese ancestry from the Honolulu Heart Program/Honolulu-Asia Aging Study (HHP/HAAS), a genetically and culturally homogeneous cohort followed for over 40 years. A Cox regression model with age as the time scale, stratified by year of birth, was used to estimate the effect of baseline height on mortality during follow-up. An analysis of height and longevity-associated variants of the key regulatory gene in the insulin/ IGF-1 signaling (IIS) pathway, FOXO3, was performed in a HHP-HAAS subpopulation. A study of fasting insulin level and height was conducted in another HHP-HAAS subpopulation. Results: A positive association was found between baseline height and all-cause mortality (RR = 1.007; 95% CI 1.003-1.011; P = 0.002) over the follow-up period. Adjustments for possible confounding variables reduced this association only slightly (RR = 1.006; 95% CI 1.002-1.010; P = 0.007). In addition, height was positively associated with all cancer mortality and mortality from cancer unrelated to smoking. A Cox regression model with time-dependent covariates showed that relative risk for baseline height on mortality increased as the population aged. Comparison of genotypes of a longevity-associated single nucleotide polymorphism in FOXO3 showed that the longevity allele was inversely associated with height. This finding was consistent with prior findings in model organisms of aging. Height was also positively associated with fasting blood insulin level, a risk factor for mortality. Regression analysis of fasting insulin level (mIU/L) on height (cm) adjusting for the age both data were collected yielded a regression coefficient of 0.26 (95% CI 0.10-0.42; P = 0.001). Conclusion: Height in mid-life is positively associated with mortality, with shorter stature predicting longer lifespan. Height was, moreover, associated with fasting insulin level and the longevity genotype of FOXO3, consistent with a mechanistic role for the IIS pathway.
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2013
Evidence from model organisms suggests that the insulin/IGF-1 signaling pathway has an important,... more Evidence from model organisms suggests that the insulin/IGF-1 signaling pathway has an important, evolutionarily conserved influence over rate of aging and thus longevity. In humans, the FOXO3 gene is the only widely replicated insulin/ IGF-1 signaling pathway gene associated with longevity across multiple populations. Therefore, we conducted a nested case-control study of other insulin/IGF-1 signaling genes and longevity, utilizing a large, homogeneous, long-lived population of American men of Japanese ancestry, well characterized for aging phenotypes. Genotyping was performed of single nucleotide polymorphisms, tagging most of the genetic variation across several genes in the insulin/IGF-1 signaling pathway or related gene networks that may be influenced by FOXO3, namely, ATF4, CBL, CDKN2, EXO1, and JUN. Two initial, marginal associations with longevity did not remain significant after correction for multiple comparisons, nor were they correlated with aging-related phenotypes.
The kidney has long been invoked in the etiology of essential hypertension. This could involve al... more The kidney has long been invoked in the etiology of essential hypertension. This could involve alterations in expression of specific genes and microRNAs (miRNAs). The aim of the present study was to identify, at the transcriptome-wide level, mRNAs and miRNAs that were differentially expressed between kidneys of 15 untreated hypertensive and 7 normotensive white male subjects of white European ancestry. By microarray technology we found 14 genes and 11 miRNAs that were differentially expressed in the medulla. We then selected and confirmed by real-time quantitative PCR expression differences for NR4A1 , NR4A2 , NR4A3 , PER1 , and SIK1 mRNAs and for the miRNAs hsa-miR-638 and hsa-let-7c. Luciferase reporter gene experiments in human kidney (HEK293) cells confirmed the predicted binding of hsa-let-7c to the 3′ untranslated region of NR4A2 mRNA. In the renal cortex we found differential expression of 46 genes and 13 miRNAs. We then confirmed expression differences for AIFM1 , AMBP , APO...
What's known on the subject? and What does the study add? • The sensitivity of the foreskin and i... more What's known on the subject? and What does the study add? • The sensitivity of the foreskin and its importance in erogenous sensitivity is widely debated and controversial. This is part of the actual public debate on circumcision for non-medical reason. Today some studies on the effect of circumcision on sexual function are available. However they vary widely in outcome.
W hen it comes to the truth on any topic, would you trust an academic expert? Or would you put yo... more W hen it comes to the truth on any topic, would you trust an academic expert? Or would you put your faith in an article by a freelance writer? … or the opinion of a lay person?
Objective-The theory that a more thinly keratinized inner foreskin leads to increased HIV-1 susce... more Objective-The theory that a more thinly keratinized inner foreskin leads to increased HIV-1 susceptibility has been based on relatively little published data. We sought to quantify the keratin thicknesses of the inner and outer foreskin to determine the plausibility of this hypothesis. Design-We took repeated measurements of the keratin layer of 16 adult male foreskins to determine if differences existed between the inner and outer foreskin. Methods-Adult foreskins were collected from consenting donors undergoing elective male circumcision for unknown medical indications in Chicago, IL. Specimens were processed, sectioned and stained for keratin using anti-filaggrin fluorescent antibodies. Slides stained with H&E were used as controls to compare to previously published studies using this method. Keratin layers were measured in a standardized fashion for each specimen. Results-Comparing our fluorescence-based analysis to previously published immunohistochemical methods revealed that our method was highly accurate for measuring foreskin keratin thickness. There was significant heterogeneity in the keratin thickness of the inner and outer aspects of the male foreskin within and between the different donors. There was no significant difference between the inner and outer foreskin keratin thickness (25.37 ± 12.51 and 20.54 ± 12.51μm respectively, p=0.451). Conclusions-We found no difference between the keratinization of the inner and outer aspects of the adult male foreskin. Keratin layers alone are unlikely to explain why uncircumcised men are at higher risk for HIV infection.
The glans of the uncircumcised men had significantly lower mean (SEM) pressure thresholds than th... more The glans of the uncircumcised men had significantly lower mean (SEM) pressure thresholds than that of the circumcised men, at 0.161 (0.078) g (P = 0.040) when controlled for age, location of measurement, type of underwear worn, and ethnicity. There were significant differences in pressure thresholds by location on the penis (P < 0.001). The most sensitive location on the circumcised penis was the circumcision scar on the ventral surface. Five locations on the uncircumcised penis that are routinely removed at circumcision had lower pressure thresholds than the ventral scar of the circumcised penis. CONCLUSIONS The glans of the circumcised penis is less sensitive to fine touch than the glans of the uncircumcised penis. The transitional region from the external to the internal prepuce is the most sensitive region of the uncircumcised penis and more sensitive than the most sensitive region of the circumcised penis. Circumcision ablates the most sensitive parts of the penis.
FOXO3 is a prominent longevity gene. To date, no-one has examined whether longevity-associated FO... more FOXO3 is a prominent longevity gene. To date, no-one has examined whether longevity-associated FOXO3 genetic variants protect against mortality in all individuals, or only in those with aging-related diseases. We therefore tested longevity-associated FOXO3 single nucleotide polymorphisms in a haplotype block for association with mortality in 3,584 elderly American men of Japanese ancestry, 2,512 with and 1,072 without a cardiometabolic disease (CMD). At baseline (1991-1993), 1,010 CMD subjects had diabetes, 1,919 had hypertension, and 738 had coronary heart disease (CHD). Follow-up until Dec 31, 2019 found that in CMDaffected individuals, longevity-associated alleles of FOXO3 were associated with significantly longer lifespan: haplotype hazard ratio 0.81 (95% CI 0.72-0.91; diabetes 0.77, hypertension 0.82, CHD 0.83). Overall, men with a CMD had higher mortality than men without a CMD (P=6x10-7). However, those men with a CMD who had the FOXO3 longevity genotype had similar survival as men without a CMD. In men without a CMD there was no association of longevity-associated alleles of FOXO3 with lifespan. Our study provides novel insights into the basis for the long-established role of FOXO3 as a longevity gene. We suggest that the FOXO3 longevity genotype increases lifespan only in at-risk individuals by protection against cardiometabolic stress.
INTRODUCTION Growth hormone (GH) and its receptor (GHR) are not only important for regulating gro... more INTRODUCTION Growth hormone (GH) and its receptor (GHR) are not only important for regulating growth, they have many other important biological functions including response to nutrients, regulation of metabolism and controlling physiological processes related to the hepatobiliary, cardiovascular, renal, gastrointestinal, and reproductive systems [1, 2]. Growth hormone signaling is an important regulator of aging. GH deficiency leads to slower growth, delayed maturation, reduced body size, and can result in attenuation of the rate of aging,
BACKGROUND The minor alleles of 3 FOXO3 single nucleotide polymorphisms (SNPs)-rs2802292, rs22533... more BACKGROUND The minor alleles of 3 FOXO3 single nucleotide polymorphisms (SNPs)-rs2802292, rs2253310, and rs2802288-are associated with human longevity. The aim of the present study was to test these SNPs for association with blood pressure (BP) and essential hypertension (EHT). METHODS In a primary study involving Americans of Japanese ancestry drawn from the Family Blood Pressure Program II we genotyped 411 female and 432 male subjects aged 40-79 years and tested for statistical association by contingency table analysis and generalized linear models that included logistic regression adjusting for sibling correlation in the data set. Replication of rs2802292 with EHT was attempted in Japanese SONIC study subjects and of each SNP in a meta-analysis of genomewide association studies of BP in individuals of European ancestry. RESULTS In Americans of Japanese ancestry, women homozygous for the longevity-associated (minor) allele of each FOXO3 SNP had 6 mm Hg lower systolic BP and 3 mm Hg lower diastolic BP compared with major allele homozygotes (Bonferroni corrected P < 0.05 and >0.05, respectively). Frequencies of minor allele homozygotes were 3.3-3.9% in women with EHT compared with 9.5-9.6% in normotensive women (P = 0.03-0.04; haplotype analysis P = 0.0002). No association with BP or EHT was evident in males. An association with EHT was seen for the minor allele of rs2802292 in the Japanese SONIC cohort (P = 0.03), while in European subjects the minor allele of each SNP was associated with higher systolic and diastolic BP. CONCLUSION Longevity-associated FOXO3 variants may be associated with lower BP and EHT in Japanese women.
The mechanistic target of rapamycin (mTOR) pathway is pivotal for cell growth. Regulatory associa... more The mechanistic target of rapamycin (mTOR) pathway is pivotal for cell growth. Regulatory associated protein of mTOR complex I (Raptor) is a unique component of this pro-growth complex. The present study tested whether variation across the raptor gene (RPTOR) is associated with overweight and hypertension. We tested 61 common (allele frequency ≥ 0.1) tagging single nucleotide polymorphisms (SNPs) that captured most of the genetic variation across RPTOR in 374 subjects of normal lifespan and 439 subjects with a lifespan exceeding 95 years for association with overweight/obesity, essential hypertension, and isolated systolic hypertension. Subjects were drawn from the Honolulu Heart Program, a homogeneous population of American men of Japanese ancestry, well characterized for phenotypes relevant to conditions of aging. Hypertension status was ascertained when subjects were 45-68 years old. Statistical evaluation involved contingency table analysis, logistic regression, and the powerful...
We read with interest a review by Deacon and Muir ('D&M') that concluded so-called 'non-therapeut... more We read with interest a review by Deacon and Muir ('D&M') that concluded so-called 'non-therapeutic' male circumcision (NTMC) of infants and children provides insufficient benefits and that risks were too high for it to be recommended in the UK [1]. Instead, they suggest delay until the boy is old enough to make his own decision. However, in contrast to the UK, policy statements by the American Academy of Pediatrics (AAP) [2] and Centers for Disease Control and Prevention (CDC) [3], finding benefits of NTMC exceed risks, are evidence-based. Flaws in D&M's arguments include reliance on small, weak, outof-date or inappropriate studies contradicted by more recent highquality evidence. Unlike systematic reviews and meta-analyses, D&M did not engage sufficiently with existing evidence. Studies cited were not rated by quality. They ignored a landmark high-quality study by CDC researchers of adverse events from 1.4 million neonatal and older age US males [4]. NTMC risk in infants was 0.4% and was 20-fold higher at age 1-9 and 10-fold higher at age ≥10. Similar values were cited in the AAP's policy statement. Thus D&M's claim of 1-5% risk may apply in non-US countries or to later circumcision. Also missing were key studies and important critiques of various publications they cited, as well as meta-analyses, and systematic reviews of benefits and risks (summarised in ref. [5]). If included, D&M's overall conclusion would have been more balanced. Instead of number-needed-to-treat (NNT) for each condition, they should have combined all such information into an overall risk-benefit analysis. An informed 'big picture' might then have emerged to better inform parents and practitioners. Several risk-benefit analyses have been published over the past decade, including ours in 'Mayo Clinic Proceedings' cited by the CDC. The only one for the UK found benefits exceeded risks by 200:1, with failure to perform NTMC in infancy likely resulting in at least one adverse medical condition among over half of uncircumcised males during their lifetime [6]. Contrary to D&M's assertion, the data we used for risk-benefit analyses were not 'over-estimates,' but came from high-quality studies. Contrary to their claim that the foreskin becomes fully retractile in 99% by age sixteen, our systematic review, involving 43 studies, included one finding full retractability was 51.1% in 1834 uncircumcised adolescent boys [7] and averaged 96.6% in men, being 92.2% in British National Servicemen [8].
Genetic variants of the kinase signaling gene MAP3K5 are associated with longevity. Here we explo... more Genetic variants of the kinase signaling gene MAP3K5 are associated with longevity. Here we explore whether the longevity-association involves protection against mortality in all individuals, or only in individuals with aging-related diseases. We tested the strongest longevity associated single nucleotide polymorphism (SNP), rs2076260, for association with mortality in 3,516 elderly American men of Japanese ancestry. At baseline (1991–1993), 2,461 had either diabetes (n=990), coronary heart disease (CHD; n=724), or hypertension (n=1,877), and 1,055 lacked any of these cardiometabolic diseases (CMDs). The men were followed from baseline until Dec 31, 2019. Longevity-associated genotype CC in a major allele homozygote model, and CC+TT in a heterozygote disadvantage model were associated with longer lifespan in individuals having a CMD (covariate-adjusted hazard ratio [HR] 1.23 [95% CI: 1.12–1.35, p=2.5x10–5] in major allele homozygote model, and 1.22 [95% CI: 1.11–1.33, p=1.10x10–5] i...
FOXO3 has been implicated in longevity in multiple populations. By DNA sequencing in long-lived i... more FOXO3 has been implicated in longevity in multiple populations. By DNA sequencing in long-lived individuals, we identified all single nucleotide polymorphisms (SNPs) in FOXO3 and showed 41 were associated with longevity. Thirteen of these had predicted alterations in transcription factor binding sites. Those SNPs appeared to be in physical contact, via RNA polymerase II binding chromatin looping, with sites in the FOXO3 promoter, and likely function together as a cis-regulatory unit. The SNPs exhibited a high degree of LD in the Asian population, in which they define a specific longevity haplotype that is relatively common. The haplotype was less frequent in whites and virtually nonexistent in Africans. We identified distant contact points between FOXO3 and 46 neighboring genes, through long-range physical contacts via CCCTC-binding factor zinc finger protein (CTCF) binding sites, over a 7.3 Mb distance on chromosome 6q21. When activated by cellular stress, we visualized movement of...
Objectives: To determine the relation between height, FOXO3 genotype and age of death in humans. ... more Objectives: To determine the relation between height, FOXO3 genotype and age of death in humans. Methods: Observational study of 8,003 American men of Japanese ancestry from the Honolulu Heart Program/Honolulu-Asia Aging Study (HHP/HAAS), a genetically and culturally homogeneous cohort followed for over 40 years. A Cox regression model with age as the time scale, stratified by year of birth, was used to estimate the effect of baseline height on mortality during follow-up. An analysis of height and longevity-associated variants of the key regulatory gene in the insulin/ IGF-1 signaling (IIS) pathway, FOXO3, was performed in a HHP-HAAS subpopulation. A study of fasting insulin level and height was conducted in another HHP-HAAS subpopulation. Results: A positive association was found between baseline height and all-cause mortality (RR = 1.007; 95% CI 1.003-1.011; P = 0.002) over the follow-up period. Adjustments for possible confounding variables reduced this association only slightly (RR = 1.006; 95% CI 1.002-1.010; P = 0.007). In addition, height was positively associated with all cancer mortality and mortality from cancer unrelated to smoking. A Cox regression model with time-dependent covariates showed that relative risk for baseline height on mortality increased as the population aged. Comparison of genotypes of a longevity-associated single nucleotide polymorphism in FOXO3 showed that the longevity allele was inversely associated with height. This finding was consistent with prior findings in model organisms of aging. Height was also positively associated with fasting blood insulin level, a risk factor for mortality. Regression analysis of fasting insulin level (mIU/L) on height (cm) adjusting for the age both data were collected yielded a regression coefficient of 0.26 (95% CI 0.10-0.42; P = 0.001). Conclusion: Height in mid-life is positively associated with mortality, with shorter stature predicting longer lifespan. Height was, moreover, associated with fasting insulin level and the longevity genotype of FOXO3, consistent with a mechanistic role for the IIS pathway.
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2013
Evidence from model organisms suggests that the insulin/IGF-1 signaling pathway has an important,... more Evidence from model organisms suggests that the insulin/IGF-1 signaling pathway has an important, evolutionarily conserved influence over rate of aging and thus longevity. In humans, the FOXO3 gene is the only widely replicated insulin/ IGF-1 signaling pathway gene associated with longevity across multiple populations. Therefore, we conducted a nested case-control study of other insulin/IGF-1 signaling genes and longevity, utilizing a large, homogeneous, long-lived population of American men of Japanese ancestry, well characterized for aging phenotypes. Genotyping was performed of single nucleotide polymorphisms, tagging most of the genetic variation across several genes in the insulin/IGF-1 signaling pathway or related gene networks that may be influenced by FOXO3, namely, ATF4, CBL, CDKN2, EXO1, and JUN. Two initial, marginal associations with longevity did not remain significant after correction for multiple comparisons, nor were they correlated with aging-related phenotypes.
The kidney has long been invoked in the etiology of essential hypertension. This could involve al... more The kidney has long been invoked in the etiology of essential hypertension. This could involve alterations in expression of specific genes and microRNAs (miRNAs). The aim of the present study was to identify, at the transcriptome-wide level, mRNAs and miRNAs that were differentially expressed between kidneys of 15 untreated hypertensive and 7 normotensive white male subjects of white European ancestry. By microarray technology we found 14 genes and 11 miRNAs that were differentially expressed in the medulla. We then selected and confirmed by real-time quantitative PCR expression differences for NR4A1 , NR4A2 , NR4A3 , PER1 , and SIK1 mRNAs and for the miRNAs hsa-miR-638 and hsa-let-7c. Luciferase reporter gene experiments in human kidney (HEK293) cells confirmed the predicted binding of hsa-let-7c to the 3′ untranslated region of NR4A2 mRNA. In the renal cortex we found differential expression of 46 genes and 13 miRNAs. We then confirmed expression differences for AIFM1 , AMBP , APO...
What's known on the subject? and What does the study add? • The sensitivity of the foreskin and i... more What's known on the subject? and What does the study add? • The sensitivity of the foreskin and its importance in erogenous sensitivity is widely debated and controversial. This is part of the actual public debate on circumcision for non-medical reason. Today some studies on the effect of circumcision on sexual function are available. However they vary widely in outcome.
W hen it comes to the truth on any topic, would you trust an academic expert? Or would you put yo... more W hen it comes to the truth on any topic, would you trust an academic expert? Or would you put your faith in an article by a freelance writer? … or the opinion of a lay person?
Objective-The theory that a more thinly keratinized inner foreskin leads to increased HIV-1 susce... more Objective-The theory that a more thinly keratinized inner foreskin leads to increased HIV-1 susceptibility has been based on relatively little published data. We sought to quantify the keratin thicknesses of the inner and outer foreskin to determine the plausibility of this hypothesis. Design-We took repeated measurements of the keratin layer of 16 adult male foreskins to determine if differences existed between the inner and outer foreskin. Methods-Adult foreskins were collected from consenting donors undergoing elective male circumcision for unknown medical indications in Chicago, IL. Specimens were processed, sectioned and stained for keratin using anti-filaggrin fluorescent antibodies. Slides stained with H&E were used as controls to compare to previously published studies using this method. Keratin layers were measured in a standardized fashion for each specimen. Results-Comparing our fluorescence-based analysis to previously published immunohistochemical methods revealed that our method was highly accurate for measuring foreskin keratin thickness. There was significant heterogeneity in the keratin thickness of the inner and outer aspects of the male foreskin within and between the different donors. There was no significant difference between the inner and outer foreskin keratin thickness (25.37 ± 12.51 and 20.54 ± 12.51μm respectively, p=0.451). Conclusions-We found no difference between the keratinization of the inner and outer aspects of the adult male foreskin. Keratin layers alone are unlikely to explain why uncircumcised men are at higher risk for HIV infection.
The glans of the uncircumcised men had significantly lower mean (SEM) pressure thresholds than th... more The glans of the uncircumcised men had significantly lower mean (SEM) pressure thresholds than that of the circumcised men, at 0.161 (0.078) g (P = 0.040) when controlled for age, location of measurement, type of underwear worn, and ethnicity. There were significant differences in pressure thresholds by location on the penis (P < 0.001). The most sensitive location on the circumcised penis was the circumcision scar on the ventral surface. Five locations on the uncircumcised penis that are routinely removed at circumcision had lower pressure thresholds than the ventral scar of the circumcised penis. CONCLUSIONS The glans of the circumcised penis is less sensitive to fine touch than the glans of the uncircumcised penis. The transitional region from the external to the internal prepuce is the most sensitive region of the uncircumcised penis and more sensitive than the most sensitive region of the circumcised penis. Circumcision ablates the most sensitive parts of the penis.
FOXO3 is a prominent longevity gene. To date, no-one has examined whether longevity-associated FO... more FOXO3 is a prominent longevity gene. To date, no-one has examined whether longevity-associated FOXO3 genetic variants protect against mortality in all individuals, or only in those with aging-related diseases. We therefore tested longevity-associated FOXO3 single nucleotide polymorphisms in a haplotype block for association with mortality in 3,584 elderly American men of Japanese ancestry, 2,512 with and 1,072 without a cardiometabolic disease (CMD). At baseline (1991-1993), 1,010 CMD subjects had diabetes, 1,919 had hypertension, and 738 had coronary heart disease (CHD). Follow-up until Dec 31, 2019 found that in CMDaffected individuals, longevity-associated alleles of FOXO3 were associated with significantly longer lifespan: haplotype hazard ratio 0.81 (95% CI 0.72-0.91; diabetes 0.77, hypertension 0.82, CHD 0.83). Overall, men with a CMD had higher mortality than men without a CMD (P=6x10-7). However, those men with a CMD who had the FOXO3 longevity genotype had similar survival as men without a CMD. In men without a CMD there was no association of longevity-associated alleles of FOXO3 with lifespan. Our study provides novel insights into the basis for the long-established role of FOXO3 as a longevity gene. We suggest that the FOXO3 longevity genotype increases lifespan only in at-risk individuals by protection against cardiometabolic stress.
INTRODUCTION Growth hormone (GH) and its receptor (GHR) are not only important for regulating gro... more INTRODUCTION Growth hormone (GH) and its receptor (GHR) are not only important for regulating growth, they have many other important biological functions including response to nutrients, regulation of metabolism and controlling physiological processes related to the hepatobiliary, cardiovascular, renal, gastrointestinal, and reproductive systems [1, 2]. Growth hormone signaling is an important regulator of aging. GH deficiency leads to slower growth, delayed maturation, reduced body size, and can result in attenuation of the rate of aging,
BACKGROUND The minor alleles of 3 FOXO3 single nucleotide polymorphisms (SNPs)-rs2802292, rs22533... more BACKGROUND The minor alleles of 3 FOXO3 single nucleotide polymorphisms (SNPs)-rs2802292, rs2253310, and rs2802288-are associated with human longevity. The aim of the present study was to test these SNPs for association with blood pressure (BP) and essential hypertension (EHT). METHODS In a primary study involving Americans of Japanese ancestry drawn from the Family Blood Pressure Program II we genotyped 411 female and 432 male subjects aged 40-79 years and tested for statistical association by contingency table analysis and generalized linear models that included logistic regression adjusting for sibling correlation in the data set. Replication of rs2802292 with EHT was attempted in Japanese SONIC study subjects and of each SNP in a meta-analysis of genomewide association studies of BP in individuals of European ancestry. RESULTS In Americans of Japanese ancestry, women homozygous for the longevity-associated (minor) allele of each FOXO3 SNP had 6 mm Hg lower systolic BP and 3 mm Hg lower diastolic BP compared with major allele homozygotes (Bonferroni corrected P < 0.05 and >0.05, respectively). Frequencies of minor allele homozygotes were 3.3-3.9% in women with EHT compared with 9.5-9.6% in normotensive women (P = 0.03-0.04; haplotype analysis P = 0.0002). No association with BP or EHT was evident in males. An association with EHT was seen for the minor allele of rs2802292 in the Japanese SONIC cohort (P = 0.03), while in European subjects the minor allele of each SNP was associated with higher systolic and diastolic BP. CONCLUSION Longevity-associated FOXO3 variants may be associated with lower BP and EHT in Japanese women.
The mechanistic target of rapamycin (mTOR) pathway is pivotal for cell growth. Regulatory associa... more The mechanistic target of rapamycin (mTOR) pathway is pivotal for cell growth. Regulatory associated protein of mTOR complex I (Raptor) is a unique component of this pro-growth complex. The present study tested whether variation across the raptor gene (RPTOR) is associated with overweight and hypertension. We tested 61 common (allele frequency ≥ 0.1) tagging single nucleotide polymorphisms (SNPs) that captured most of the genetic variation across RPTOR in 374 subjects of normal lifespan and 439 subjects with a lifespan exceeding 95 years for association with overweight/obesity, essential hypertension, and isolated systolic hypertension. Subjects were drawn from the Honolulu Heart Program, a homogeneous population of American men of Japanese ancestry, well characterized for phenotypes relevant to conditions of aging. Hypertension status was ascertained when subjects were 45-68 years old. Statistical evaluation involved contingency table analysis, logistic regression, and the powerful...
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Papers by Brian Morris