Novel protective effect of the FOXO3 longevity genotype on mechanisms of cellular aging in Okinawans.

The genetic association of FOXO3 genotypes with human longevity is well established, although the mechanism is not fully understood. We now report on the relationship of the FOXO3 longevity variant rs2802292 with telomere length, telomerase activity, FOXO3 expression, and inflammatory cytokine levels in men and women. In agreement with earlier work, the FOXO3 longevity variant conferred protection against telomere shortening of peripheral blood mononuclear cells from adults aged 55 years and older. This was accompanied by higher levels of telomerase activity in mononuclear cells for carriers of the longevity-associated FOXO3 G-allele of SNP rs2802292 (P = 0.015). FOXO3 mRNA expression increased slightly with age in both young (P = 0.02) and old (P = 0.08) G-allele carriers. Older female G-allele carriers displayed a modest decline in levels of pro-inflammatory cytokine IL-6 with age (P = 0.07). In contrast, older male G-allele carriers displayed an age-dependent increase in levels of anti-inflammatory cytokine IL-10 with age (P = 0.04). Thus, FOXO3 may act through several different pro-longevity mechanisms, which may differ by age and sex.

FOXO3 longevity genotype attenuates the impact of hypertension on cerebral microinfarct risk.

OBJECTIVE: The G -allele of FOXO3 SNP rs2802292 , which is associated with human resilience and longevity, has been shown to attenuate the impact of hypertension on the risk of intracerebral hemorrhage (ICH). We sought to determine whether the FOXO3 G -allele similarly attenuates the impact of hypertension on the risk of cerebral microinfarcts (CMI). METHODS: From a prospective population-based cohort of American men of Japanese ancestry from the Kuakini Honolulu Heart Program (KHHP) and Kuakini Honolulu-Asia Aging Study (KHAAS) that had brain autopsy data, age-adjusted prevalence of any CMI on brain autopsy was assessed. Logistic regression models, adjusted for age at death, cardiovascular risk factors, FOXO3 and APOE-ε4 genotypes, were utilized to determine the predictors of any CMI. Interaction of FOXO3 genotype and hypertension was analyzed. RESULTS: Among 809 men with complete data, 511 (63.2%) participants had evidence of CMI. A full multivariable model demonstrated that BMI [odds ratio (OR) 1.07, 95% confidence interval (CI) 1.01-1.14, P  = 0.015) was the only predictor of CMI, while hypertension was a borderline predictor (OR 1.44, 95% CI 1.00-2.08, P  = 0.052). However, a significant interaction between FOXO3 G -allele carriage and hypertension was observed ( P  = 0.020). In the stratified analyses, among the participants without the longevity-associated FOXO3 G -allele, hypertension was a strong predictor of CMI (OR 2.25, 95% CI 1.34-3.77, P  = 0.002), while among those with the longevity-associated FOXO3 G -allele, hypertension was not a predictor of CMI (OR 0.88, 95% CI 0.51-1.54, P  = 0.66). CONCLUSION: The longevity-associated FOXO3 G -allele mitigates the impact of hypertension on the risk of CMI.

Incidence of Alzheimer's Disease in Men with Late-Life Hypertension Is Ameliorated by FOXO3 Longevity Genotype.

BACKGROUND: It is well established that mid-life hypertension increases risk of dementia, whereas the association of late-life hypertension with dementia is unclear. OBJECTIVE: To determine whether FOXO3 longevity-associated genotype influences the association between late-life hypertension and incident dementia. METHODS: Subjects were 2,688 American men of Japanese ancestry (baseline age: 77.0±4.1 years, range 71-93 years) from the Kuakini Honolulu Heart Program. Status was known for FOXO3 rs2802292 genotype, hypertension, and diagnosis of incident dementia to 2012. Association of FOXO3 genotype with late-life hypertension and incident dementia, vascular dementia (VaD) and Alzheimer's disease (AD) was assessed using Cox proportional hazards models. RESULTS: During 21 years of follow-up, 725 men were diagnosed with all-cause dementia, 513 with AD, and 104 with VaD. A multivariable Cox model, adjusting for age, education, APOEɛ4, and cardiovascular risk factors, showed late-life hypertension increased VaD risk only (HR = 1.71, 95% CI = 1.08-2.71, p = 0.022). We found no significant protective effect of FOXO3 longevity genotype on any type of dementia at the population level. However, in a full Cox model adjusting for age, education, APOEɛ4, and other cardiovascular risk factors, there was a significant interaction effect of late-life hypertension and FOXO3 longevity genotype on incident AD (ß= -0.52, p = 0.0061). In men with FOXO3 rs2802292 longevity genotype (TG/GG), late-life hypertension showed protection against AD (HR = 0.72; 95% CI = 0.55-0.95, p = 0.021). The non-longevity genotype (TT) (HR = 1.16; 95% CI = 0.90-1.51, p = 0.25) had no protective effect. CONCLUSION: This longitudinal study found late-life hypertension was associated with lower incident AD in subjects with FOXO3 genotype.

Vascular endothelial growth factor receptor 1 gene (FLT1) longevity variant increases lifespan by reducing mortality risk posed by hypertension.

Longevity is written into the genes. While many so-called "longevity genes" have been identified, the reason why particular genetic variants are associated with longer lifespan has proven to be elusive. The aim of the present study was to test the hypothesis that the strongest of 3 adjacent longevity-associated single nucleotide polymorphisms - rs3794396 - of the vascular endothelial growth factor receptor 1 gene, FLT1, may confer greater lifespan by protecting against mortality risk from one or more adverse medical conditions of aging - namely, hypertension, coronary heart disease (CHD), stroke, and diabetes. In a prospective population-based longitudinal study we followed 3,471 American men of Japanese ancestry living on Oahu, Hawaii, from 1965 until death or to the end of December 2019 by which time 99% had died. Cox proportional hazards models were used to assess the association of FLT1 genotype with longevity for 4 genetic models and the medical conditions. We found that, in major allele recessive and heterozygote disadvantage models, genotype GG ameliorated the risk of mortality posed by hypertension, but not that posed by having CHD, stroke or diabetes. Normotensive subjects lived longest and there was no significant effect of FLT1 genotype on their lifespan. In conclusion, the longevity-associated genotype of FLT1 may confer increased lifespan by protecting against mortality risk posed by hypertension. We suggest that FLT1 expression in individuals with longevity genotype boosts vascular endothelial resilience mechanisms to counteract hypertension-related stress in vital organs and tissues.

The Inflation Reduction Act and Out-of-Pocket Drug Costs for Medicare Beneficiaries With Cardiovascular Disease.

BACKGROUND: High out-of-pocket costs can impede access to guideline-directed cardiovascular drugs. The 2022 Inflation Reduction Act (IRA) will eliminate catastrophic coinsurance and cap annual out-of-pocket costs for Medicare Part D patients by 2025. OBJECTIVES: This study sought to estimate the IRA's impact on out-of-pocket costs for Part D beneficiaries with cardiovascular disease. METHODS: The investigators chose 4 cardiovascular conditions that frequently require high-cost guideline-recommended drugs: severe hypercholesterolemia; heart failure with reduced ejection fraction (HFrEF); HFrEF with atrial fibrillation (AF); and cardiac transthyretin amyloidosis. This study included 4,137 Part D plans nationwide and compared projected annual out-of-pocket drug costs for each condition in 2022 (baseline), 2023 (rollout), 2024 (5% catastrophic coinsurance eliminated), and 2025 ($2,000 cap on out-of-pocket costs). RESULTS: In 2022, mean projected annual out-of-pocket costs were $1,629 for severe hypercholesterolemia, $2,758 for HFrEF, $3,259 for HFrEF with AF, and $14,978 for amyloidosis. In 2023, the initial IRA rollout will not significantly change out-of-pocket costs for the 4 conditions. In 2024, elimination of 5% catastrophic coinsurance will lower out-of-pocket costs for the 2 costliest conditions: HFrEF with AF ($2,855, 12% reduction) and amyloidosis ($3,468, 77% reduction). By 2025, the $2,000 cap will lower out-of-pocket costs for all 4 conditions to $1,491 for hypercholesterolemia (8% reduction), $1,954 for HFrEF (29% reduction), $2,000 for HFrEF with AF (39% reduction), and $2,000 for cardiac transthyretin amyloidosis (87% reduction). CONCLUSIONS: The IRA will reduce Medicare beneficiaries' out-of-pocket drug costs for the selected cardiovascular conditions by 8% to 87%. Future studies should assess the IRA's impact on adherence to guideline-directed cardiovascular therapies and health outcomes.

Proteomic basis of mortality resilience mediated by FOXO3 longevity genotype.

FOXO3 is a ubiquitous transcription factor expressed in response to cellular stress caused by nutrient deprivation, inflammatory cytokines, reactive oxygen species, radiation, hypoxia, and other factors. We showed previously that the association of inherited FOXO3 variants with longevity was the result of partial protection against mortality risk posed by aging-related life-long stressors, particularly cardiometabolic disease. We then referred to the longevity-associated genotypes as conferring "mortality resilience." Serum proteins whose levels change with aging and are associated with mortality risk may be considered as "stress proteins." They may serve as indirect measures of life-long stress. Our aims were to (1) identify stress proteins that increase with aging and are associated with an increased risk of mortality, and (2) to determine if FOXO3 longevity/resilience genotype dampens the expected increase in mortality risk they pose. A total of 4500 serum protein aptamers were quantified using the Somalogic SomaScan proteomics platform in the current study of 975 men aged 71-83 years. Stress proteins associated with mortality were identified. We then used age-adjusted multivariable Cox models to investigate the interaction of stress protein with FOXO3 longevity-associated rs12212067 genotypes. For all the analyses, the p values were corrected for multiple comparisons by false discovery rate. This led to the identification of 44 stress proteins influencing the association of FOXO3 genotype with reduced mortality. Biological pathways were identified for these proteins. Our results suggest that the FOXO3 resilience genotype functions by reducing mortality in pathways related to innate immunity, bone morphogenetic protein signaling, leukocyte migration, and growth factor response.

Weak Social Networks in Late Life Predict Incident Alzheimer's Disease: The Kuakini Honolulu-Asia Aging Study.

BACKGROUND: We assessed 10-year longitudinal associations between late-life social networks and incidence of all-cause dementia (ACD), Alzheimer's disease (AD), and vascular dementia (VaD) in Japanese-American men. METHODS: We prospectively analyzed, from baseline (1991-1993) through 1999-2000, 2636 initially nondemented Kuakini Honolulu-Asia Aging Study participants who remained dementia-free during the first 3 years of follow-up. Global cognition was evaluated by the Cognitive Abilities Screening Instrument (CASI); depressive symptoms by the 11-item Center for Epidemiologic Studies Depression (CES-D) Scale; and social networks by the Lubben Social Network Scale (LSNS). Median split of LSNS scores defined weak/strong social network groups. A panel of neurologists and geriatricians diagnosed and classified dementia; AD and VaD diagnoses comprised cases in which AD or VaD, respectively, were considered the primary cause of dementia. RESULTS: Median (range) baseline age was 77 (71-93) years. Participants with weak (LSNS score ≤29) versus strong (>29) social networks had higher age-adjusted incidence (in person-years) of ACD (12.6 vs. 8.7; p = .014) and AD (6.7 vs. 4.0; p = .007) but not VaD (2.4 vs. 1.4; p = .15). Kaplan-Meier curves showed a lower likelihood of survival free of ACD (log-rank p < .0001) and AD (p = .0006) for men with weak networks. In Cox proportional hazards models adjusting for age, education, APOE ɛ4, prevalent stroke, depressive symptoms, and CASI score (all at baseline), weak networks predicted increased incidence of ACD (hazard ratio [HR] = 1.52, p = .009) and AD (HR = 1.67, p = .014) but not VaD (p > .2). CONCLUSION: Weak social networks may heighten the risk of dementia and AD, underscoring the need to promote social connectedness in older adults.

Forkhead box O3 longevity genotype may attenuate the impact of hypertension on risk of intracerebral haemorrhage.

OBJECTIVE: Since the G allele of forkhead box O3 ( FOXO3 ) single nucleotide polymorphism (SNP) rs2802292 is associated with resilience and longevity, ostensibly by mitigating the adverse effects of chronic cardiometabolic stress on mortality, our aim was to determine the association between the FOXO3 SNP rs2802292 genotype and risk of hypertension-mediated intracerebral haemorrhage (ICH). METHODS: From a prospective population-based cohort of Japanese American men from the Kuakini Honolulu Heart Program (KHHP), age-adjusted prevalence of ICH by hypertension was assessed for the whole cohort after stratifying by FOXO3 genotype. Cox regression models, adjusted for age, cardiovascular risk factors and, FOXO3 and APOE genotypes, were utilized to determine relative risk of hypertension's effect on ICH. All models were created for the whole cohort and stratified by FOXO3 G -allele carriage vs. TT genotype. RESULTS: Among 6469 men free of baseline stroke, FOXO3 G -allele carriage was seen in 3009 (46.5%) participants. Overall, 183 participants developed ICH over the 34-year follow-up period. Age-adjusted ICH incidence was 0.90 vs. 1.32 per 1000 person-years follow-up in those without and with hypertension, respectively ( P  = 0.002). After stratifying by FOXO3 genotype, this association was no longer significant in G allele carriers. In the whole cohort, hypertension was an independent predictor of ICH (relative risk [RR] = 1.70, 95% confidence interval [CI] 1.25, 2.32; P  = 0.0007). In stratified analyses, hypertension remained an independent predictor of ICH among the FOXO3 TT -genotype group (RR = 2.02, 95% CI 1.33, 3.07; P  = 0.001), but not in FOXO3 G -allele carriers (RR = 1.39, 95% CI 0.88, 2.19; P  = 0.15). CONCLUSIONS: The longevity-associated FOXO3   G allele may attenuate the impact of hypertension on ICH risk.

The Association Between Longevity-Associated FOXO3 Allele and Heart Disease in Septuagenarians and Octogenarians: The SONIC Study.

The G allele of FOXO3 gene (single-nucleotide polymorphism; rs2802292) is strongly associated with human longevity. However, knowledge of the effect of FOXO3 in older populations, men or women, with heart disease is limited. This cross-sectional study in Japan included 1836 older adults in the 70- and 80-year-old groups. DNA samples isolated from buffy coat samples of peripheral blood were used to genotype FOXO3 (rs2802292). Self-reports were used to obtain heart disease data according to physician diagnosis. Multiple logistic regression was used to test the association by adjusting for the traditional risk factor of heart disease. The prevalence of heart disease in women FOXO3 G-allele carriers was higher than noncarriers (16.7% vs 11.6%, p = .022). The prevalence of coronary heart disease was lower for FOXO3 G carriers in the 70-year-old group for both sexes (men: 9.3% vs 4.3%, p = .042 and women: 10% vs 9%, p = .079, respectively). The G allele was negatively associated with heart disease after adjusting for diabetes, hypertension, dyslipidemia, and smoking in men (odds ratio [OR] = 0.70, 95% confidence intervals [CIs], 0.49-0.99, p = .046), although the association was weaker after full adjustment. In contrast, women carriers of the FOXO3 G allele showed a positive association with heart disease after total adjustment (OR = 1.49, 95% CI, 1.00-2.21, p = .049). In conclusion, the longevity-associated G allele of FOXO3 was observed to have contrasting associations with heart disease prevalence according to sex in older Japanese. To further confirm this association, a longitudinal study and a large sample size will be required.

Association with Longevity of Phosphatidylinositol 3-Kinase Regulatory Subunit 1 Gene Variants Stems from Protection against Mortality Risk in Men with Cardiovascular Disease.

INTRODUCTION: Genetic variation in the phosphatidylinositol 3-kinase reregulatory subunit 1 gene (PIK3R1) is associated with longevity. OBJECTIVE: The aim of the study was to determine whether cardiovascular disease (CVD) affects this association. METHODS: We performed a longitudinal study of longevity-associated PIK3R1 single-nucleotide polymorphism rs7709243 genotype by CVD status in 3,584 elderly American men of Japanese ancestry. RESULTS: At baseline (1991-1993), 2,254 subjects had CVD and 1,314 did not. The follow-up until Dec 31, 2019 found that overall, men with a CVD had higher mortality than men without a CVD (p = 1.7 × 10-5). However, survival curves of CVD subjects differed according to PIK3R1 genotype. Those with longevity-associated PIK3R1 TT/CC had survival curves similar to those of subjects without a CVD (p = 0.11 for TT/CC, and p = 0.054 for TC), whereas survival curves for CVD subjects with the CT genotype were significantly attenuated compared with survival curves of subjects without a CVD (p = 0.0000012 compared with TT/CC, and p = 0.0000028 compared with TC). Men without CVD showed no association of longevity-associated genotype with life span (p = 0.58). Compared to subjects without any CVD, hazard ratios for mortality risk were 1.26 (95% CI, 1.14-1.39; p = 0.0000043) for CT subject with CVD and 1.07 (95% CI 0.99-1.17; p = 0.097) for CC/TT subjects with CVD. There was no genotypic effect on life span for 1,007 subjects with diabetes and 486 with cancer. CONCLUSION: Our study provides novel insights into the basis for PIK3R1 as a longevity gene. We suggest that the PIK3R1 longevity genotype attenuates mortality risk in at-risk individuals by protection against cellular stress caused by CVD.

Closing the Part D Coverage Gap and Out-of-Pocket Costs for Multiple Sclerosis Drugs.

OBJECTIVE: To determine whether closing the Part D coverage gap (donut hole) between 2010 and 2019 lowered patients' out-of-pocket costs for disease-modifying therapies (DMTs) for multiple sclerosis (MS). METHODS: Using nationwide Medicare Formulary and Drug Pricing Files, we analyzed Part D drug benefit design and DMT prices in 2010, 2016, and 2019. We calculated average monthly list prices for DMTs available in each year (4 DMTs in 2010, 11 DMTs in 2016, and 14 DMTs in 2019). We projected patients' annual out-of-pocket cost for each DMT alone under a standard Part D plan in that year. We estimated potential savings attributable to closing the coverage gap between 2010 and 2019 (beneficiaries' cost sharing dropped from 100% to 25%) under 3 scenarios: no increase in price, an inflation-indexed price increase (3% annually), and the observed price increase. RESULTS: Median monthly DMT prices rose from $2,804 to $5,987 to $7,009 over the years 2010, 2016, and 2019, respectively. Median projected annual out-of-pocket costs rose from $5,916 to $6,229 to $6,618. With unchanged or inflation-indexed DMT price changes, closing the coverage gap would have reduced annual out-of-pocket costs by $2,260 (38% reduction) and $1,744 (29% reduction), respectively. Despite having the lowest monthly price, generic glatiramer acetate had among the highest out-of-pocket costs ($6,731 to $6,939 a year) in 2019. CONCLUSIONS: Medicare Part D beneficiaries can pay thousands of dollars yearly out of pocket for DMTs. Closing the Part D coverage gap did not reduce out-of-pocket costs for patients because of simultaneous increases in DMT prices.

Association of growth hormone receptor gene variant with longevity in men is due to amelioration of increased mortality risk from hypertension.

The single nucleotide polymorphism (SNP) rs4130113 of the growth hormone receptor gene (GHR) is associated with longevity. Here we explored whether longevity-associated genotypes protect against mortality in all individuals, or only in individuals with aging-related diseases. Rs4130113 genotypes were tested for association with mortality in 3,557 elderly American men of Japanese ancestry. At baseline (1991-1993), 1,000 had diabetes, 730 had coronary heart disease (CHD), 1,901 had hypertension, 485 had cancer, and 919 lacked these diseases. The men were followed from baseline until Dec 31, 2019 or death (mean 10.8 ± 6.5 SD years, range 0.01-28.8 years; 99.0% deceased by that date). In a heterozygote disadvantage model, longevity-associated genotypes were associated with significantly lower mortality risk in individuals having hypertension (covariate-adjusted hazard ratio [HR] 0.83 [95% CI: 0.76-0.93, p = 4.3 x10-4]. But in individuals with diabetes, CHD, and cancer there was no genotypic difference in lifespan. As expected, normotensive men outlived men with hypertension (p = 0.036). There was no effect, however, of genotypic difference on lifespan in normotensive men (p = 0.11). We found that SNP rs4130113 potentially influenced the binding of transcription factors E2A, MYF, NRSF, TAL1, and TCF12 so as to alter GHR expression. We propose that in individuals with hypertension, longevity-associated genetic variation in GHR enhances cell resilience mechanisms to help protect against cellular stress caused by hypertension. As a result, hypertension-affected men who possess the longevity-associated genetic variant of GHR live as long as normotensive men.

Factors Associated with Lower Cognitive Performance Scores Among Older Japanese Men in Hawaii and Japan.

BACKGROUND: Few studies have compared factors related to cognitive function among people with similar genetic backgrounds but different lifestyles. OBJECTIVE: We aimed to identify factors related to lower cognitive scores among older Japanese men in two genetically similar cohorts exposed to different lifestyle factors. METHODS: This cross-sectional study of community-dwelling Japanese men aged 71-81 years included 2,628 men enrolled in the Kuakini Honolulu-Asia Aging Study based in Hawaii and 349 men in the Shiga Epidemiological Study of Subclinical Atherosclerosis based in Japan. We compared participant performance through Cognitive Abilities Screening Instrument (CASI) assessment in Hawaii (1991-1993) and Japan (2009-2014). Factors related to low cognitive scores (history of cardiovascular disease, cardiometabolic factors, and lifestyle factors) were identified with questionnaires and measurements. Multivariable logistic regression analysis was used to calculate the adjusted odds ratios (ORs) of a low (< 82) CASI score based on different factors. RESULTS: CASI scores were lower in Hawaii than in Japan [21.2%(n = 556) versus 12.3%(n = 43), p < 0.001], though this was not significant when adjusted for age and educational attainment (Hawaii 20.3%versus Japan 17.9%, p = 0.328). History of stroke (OR = 1.65, 95%confidence interval = 1.19-2.29) was positively associated with low cognitive scores in Hawaii. Body mass index ≥25 kg/m2 tended to be associated with low cognitive scores in Japan; there was a significant interaction between the cohorts. CONCLUSION: Cognitive scores differences between cohorts were mostly explained by differences in educational attainment. Conversely, cardiovascular diseases and cardiometabolic factors differentially impacted cognitive scores among genetically similar older men exposed to different lifestyle factors.

Lifespan extension conferred by mitogen-activated protein kinase kinase kinase 5 (MAP3K5) longevity-associated gene variation is confined to at-risk men with a cardiometabolic disease.

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] in heterozygote disadvantage model). For diabetes, hypertension and CHD, HR p-values were 0.019, 0.00048, 0.093, and 0.0024, 0.00040, 0.0014, in each respective genetic model. As expected, men without a CMD outlived men with a CMD (p=1.9x10-6). There was, however, no difference in lifespan by genotype in men without a CMD (p=0.21 and 0.86, respectively, in each genetic model). In conclusion, we propose that in individuals with a cardiometabolic disease, longevity-associated genetic variation in MAP3K5 enhances resilience mechanisms in cells and tissues to help protect against cardiometabolic stress caused by CMDs. As a result, men with CMD having longevity genotype live as long as all men without a CMD.

FOXO3 longevity genotype mitigates the increased mortality risk in men with a cardiometabolic disease.

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 CMD-affected 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.

Medicare Part D and Cost-Sharing for Antiretroviral Therapy and Preexposure Prophylaxis.

Importance: The 2019 federal Ending the HIV Epidemic initiative requires a vast expansion of access to antiretroviral therapy (ART) and preexposure prophylaxis (PrEP) for HIV treatment and prevention. However, high prices for ART and PrEP can reduce their affordability and use. Medicare covers 1 in 4 persons living with HIV, and the Medicare Part D drug benefit imposes complicated cost-sharing between patients and other stakeholders. Objective: To determine how the Medicare Part D design distributes the cost burden for ART and PrEP between patients, insurance plans, manufacturers, and Medicare. Design and Setting: Nationwide cross-sectional analyses of first quarter 2019 Medicare formulary and pricing files for 3326 Part D plans were performed. These files contain drug benefit data, including prices and cost-sharing requirements. Main Outcomes and Measures: For 18 ART and 2 PrEP regimens, the out-of-pocket costs for patients and the cost borne by plans, manufacturers, and Medicare were projected for 1 year of treatment or prevention under a 2019 standard Medicare Part D insurance plan. Analyses assumed that patients used the ART or PrEP regimen and no other medications. Results: In 2019, ART prices ranged from $24 010 to $46 770 annually (median price, $35 780), with patients projected to pay 9% to 14% of the cost ($3270-$4350), insurance plans 18% to 24% ($5340-$8450), manufacturers 6% to 11% ($2370-$2750), and Medicare 53% to 67% ($12 770-$31 270). The price of PrEP was $20 570 annually, with patients contributing 15% ($2990), insurance plans 22% ($4570), manufacturers 13% ($2750), and Medicare 50% ($10 260). For beneficiaries with low-income subsidies that cover all patient cost-sharing, Medicare would assume 67% to 76% of ART costs and 65% of PrEP costs. Conclusions and Relevance: Medicare Part D mandates universal ART and PrEP coverage, but high prices (>$35 000 annually for ART and>$20 000 annually for PrEP) and the design of Part D can jeopardize affordability for patients and place most of the cost burden on taxpayers. Under a standard Medicare Part D benefit, patients pay $3000 to $4000 out-of-pocket yearly, unless they qualify for low-income subsidies, and half to two-thirds of the cost of ART and PrEP is borne by Medicare rather than insurance plans or manufacturers. To end the HIV epidemic by 2030, it appears that policies must address both high drug prices and revamp Medicare Part D cost-sharing.