Sleep duration in midlife and old age and risk of mortality over a 48-year follow-up: The Helsinki businessmen study (HBS) cohort.

OBJECTIVES: Both short and long sleep duration have been associated with increased mortality, but there are few truly long-term studies. STUDY DESIGN: This is a cohort study of 2504 men born between 1919 and 1934. In 1974-1975 (mean age 48), participants underwent baseline clinical examinations and sleep duration assessments. A follow-up examination took place 35 years later, in 2010 (mean age 82). MAIN OUTCOME MEASURE: All-cause mortality data from baseline and from old age were collected through to December 31, 2022. RESULTS: At baseline, short sleep duration (≤6 h per night), normal sleep duration (>6 and ≤ 8 h), and long sleep duration (>8 h) was reported by 266, 2019 and 219 men, respectively. Men with short sleep duration had higher levels of smoking, alcohol consumption, body mass index, and poorer self-rated health than those with normal sleep duration. During the 48-year follow-up, 2287 men died. The unadjusted hazard ratio for mortality was 1.20 (95 % confidence interval [CI] 1.05-1.37) for short compared with normal sleep duration, but this association vanished after adjustments (1.01, 95 % CI 0.87-1.17). In old age, the corresponding hazard ratios were 1.41 (1.16-1.72) and 1.19 (0.94-1.51) for short sleep duration and 1.33 (1.09-1.63) and 1.31 (1.02-1.67) for long sleep duration. CONCLUSIONS: In a comprehensive lifespan follow-up, the modestly increased mortality among men with short sleep duration in midlife was attributed to unhealthy lifestyle factors. In old age both long and short sleep duration seemed to be associated with modestly increased mortality. CLINICALTRIALS: gov identifier for the HBS: NCT02526082.

The shared ancestry between the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles using haplotype sharing trees and HAPTK.

The C9orf72 hexanucleotide repeat expansion (HRE) is a common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The inheritance is autosomal dominant, but a high proportion of subjects with the mutation are simplex cases. One possible explanation is de novo expansions of unstable intermediate-length alleles (IAs). Using haplotype sharing trees (HSTs) with the haplotype analysis tool kit (HAPTK), we derived majority-based ancestral haplotypes of HRE samples and discovered that IAs containing ≥18-20 repeats share large haplotypes in common with the HRE. Using HSTs of HRE and IA samples, we demonstrate that the longer IA haplotypes are largely indistinguishable from HRE haplotypes and that several ≥18-20 IA haplotypes share over 5 Mb (>600 markers) haplotypes in common with the HRE haplotypes. These analysis tools allow physical understanding of the haplotype blocks shared with the majority-based ancestral haplotype. Our results demonstrate that the haplotypes with longer IAs belong to the same pool of haplotypes as the HRE and suggest that longer IAs represent potential premutation alleles.

Midlife cardiovascular health factors as predictors of retirement age, work-loss years, and years spent in retirement among older businessmen.

Cardiovascular disease (CVD) is one of the leading causes of premature retirement. However, the relationship between CVD risk factors and workforce participation is not well known. We studied the relationship between midlife CVD risk, age at retirement, work-loss years, and survival in retirement. Middle-aged Finnish men (initial n = 3490, mean age = 47.8 years) were assessed for CVD risk factors and general health in the 1970s. They worked as business executives and provided information on their retirement status in the year 2000. Survival was followed up to the 9th decade of life with a follow-up of up to 44 years. Work-loss years were calculated as death or retirement occurring at age ≤ 65 years. Smoking, body mass index, and alcohol use were used as covariates, excluding models of CVD risk, which were adjusted for alcohol use only. Higher risk of 10-year fatal CVD was associated with 0.32 more years (relative risk < 1 vs. 1, covariate-adjusted ß = 0.32, 95% CI = 0.13, 0.53) of work-loss. Higher risk of 5-year incident (covariate-adjusted time-constant HR = 1.32, 95% CI = 1.19, 1.47) and 10-year fatal (covariate-adjusted time-dependent HR = 1.55, 95% CI = 1.30, 1.85) CVD in midlife were associated with fewer years spent in retirement. Poorer self-rated health and physical fitness and higher levels of triglycerides were associated with increased hazard of earlier retirement, more work-loss years, and fewer years spent in retirement. Poorer health and greater midlife CVD risk may be associated with earlier exit from the workforce and fewer years spent in retirement. Management of CVD risk in midlife may support people to work longer.

High cholesterol absorption: A risk factor of atherosclerotic cardiovascular diseases?

Lowering elevated low-density lipoprotein cholesterol (LDL-C) concentrations reduces the risk of atherosclerotic cardiovascular diseases (ASCVDs). However, increasing evidence suggests that cholesterol metabolism may also be involved in the risk reduction of ASCVD events. In this review, we discuss if the different profiles of cholesterol metabolism, with a focus on high cholesterol absorption, are atherogenic, and what could be the possible mechanisms. The potential associations of cholesterol metabolism and the risk of ASCVDs are evaluated from genetic, metabolic, and population-based studies and lipid-lowering interventions. According to these studies, loss-of-function genetic variations in the small intestinal sterol transporters ABCG5 and ABCG8 result in high cholesterol absorption associated with low cholesterol synthesis, low cholesterol elimination from the body, and a high risk of ASCVDs. In contrast, loss-of-function genetic variations in another intestinal sterol transporter, NPC1L1 result in low cholesterol absorption associated with high cholesterol synthesis, elevated cholesterol elimination from the body, and low risk of ASCVDs. Statin monotherapy is not sufficient to reduce the ASCVD risk in cases of high cholesterol absorption, and these individuals need combination therapy of statin with cholesterol absorption inhibition. High cholesterol absorption, i.e., >60%, is estimated to occur in approximately one third of a population, so taking it into consideration is important to optimise lipid-lowering therapy to prevent atherosclerosis and reduce the risk of ASCVD events.

C9orf72 hexanucleotide repeat allele tagging SNPs: Associations with ALS risk and longevity.

C9orf72 hexanucleotide repeat expansion is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 locus may harbor residual risk outside the hexanucleotide repeat expansion, but the evidence is conflicting. Here, we first compared 683 unrelated amyotrophic lateral sclerosis cases and 3,196 controls with Finnish ancestry to find best single nucleotide polymorphisms that tag the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles. Rs2814707 was the best tagging single nucleotide polymorphisms for intermediate-length alleles with ≥7 repeats (p = 5 × 10-307) and rs139185008 for the hexanucleotide repeat expansion (p = 7 × 10-114) as well as alleles with ≥20 repeats. rs139185008*C associated with amyotrophic lateral sclerosis after removing cases with the hexanucleotide repeat expansion, especially in the subpopulation homozygous for the rs2814707*T (p = 0.0002, OR = 5.06), which supports the concept of residual amyotrophic lateral sclerosis risk at the C9orf72 haplotypes other than the hexanucleotide repeat expansion. We then leveraged Finnish biobank data to test the effects of rs2814707*T and rs139185008*C on longevity after removing individuals with amyotrophic lateral sclerosis / frontotemporal dementia diagnoses. In the discovery cohort (n = 230,006), the frequency of rs139185008*C heterozygotes decreased significantly with age in the comparisons between 50 and 80 years vs. >80 years (p = 0.0005) and <50 years vs. >80 years (p = 0.0001). The findings were similar but less significant in a smaller replication cohort (2-sided p = 0.037 in 50-80 years vs. >80 years and 0.061 in <50 years vs. >80 years). Analysis of the allele frequencies in 5-year bins demonstrated that the decrease of rs139185008*C started after the age of 70 years. The hexanucleotide repeat expansion tagging single nucleotide polymorphisms decreasing frequency with age suggests its' association with age-related diseases probably also outside amyotrophic lateral sclerosis / frontotemporal dementia.

Management of Older Patients with Head and Neck Cancer: A Comprehensive Review.

The projected increase in life expectancy over the next few decades is expected to result in a rise in age-related diseases, including cancer. Head and neck cancer (HNC) is a worldwide health problem with high rates of morbidity and mortality. In this report, we have critically reviewed the literature reporting the management of older patients with HNC. Older adults are more prone to complications and toxicities secondary to HNC treatment, especially those patients who are frail or have comorbidities. Thus, this population should be screened prior to treatment for such predispositions to maximize medical management of comorbidities. Chronologic age itself is not a reason for choosing less intensive treatment for older HNC patients. Whenever possible, also older patients should be treated according to the best standard of care, as nonstandard approaches may result in increased treatment failure rates and mortality. The treatment plan is best established by a multidisciplinary tumor board with shared decision-making with patients and family. Treatment modifications should be considered for those patients who have severe comorbidities, evidence of frailty (low performance status), or low performance status or those who refuse the recommendations of the tumor board.

Determinants of a sense of insecurity among home-dwelling older people.

Aims: A sense of insecurity may have an impact on older people's well-being and their courage to engage actively in meaningful activities. Studies on a sense of insecurity among older people are scarce. The aim of this study was to determine the extent to which home-dwelling older adults perceive their life as being insecure and how a sense of insecurity is associated with their health, functional status, active social engagement, well-being and perceptions of the societal treatment of older people. Methods: This study is part of the Helsinki Aging Study, a cohort study ongoing since 1989. Data were collected using a postal questionnaire that was mailed in 2019 to a random sample of home-dwelling older people ⩾75 years of age living in Helsinki (N=2917; response rate 74%). The questionnaire inquired about the respondents' sense of security/insecurity, and they were subcategorised into those feeling secure and those feeling insecure based on their answers. Results: Seven per cent of respondents felt insecure in their lives. In a stepwise logistic regression analysis, loneliness, living alone and perceived poor societal treatment of older people were associated with a sense of insecurity, while having good self-rated health, having children and meeting friends at least weekly were associated with lower odds of insecurity. Conclusions: Our findings highlight the importance of recognising and combating loneliness, social isolation and societal ageism in order to reduce insecurity among older people and to support their active engagement in life.

Temporal Trends Over Two Decades in the Use of Anticholinergic Drugs Among Older Community-Dwelling People in Helsinki, Finland.

BACKGROUND: Knowledge of the adverse effects of drugs with anticholinergic properties (DAPs) has increased in recent decades. However, research on the temporal trends of the clinical use of DAPs is still sparse. OBJECTIVES: The aim of this study was to investigate the temporal trends of DAP use over two decades in the older community-dwelling population and to explore the medication classes contributing to the use of DAPs. METHODS: The study involved random samples of ≥ 75-year-old community-dwelling Helsinki citizens in 1999, 2009, and 2019 from the Helsinki Ageing Study. A postal questionnaire inquired about their health, functioning, and medications. The medications were categorized as DAPs according to Duran's list. In addition, we grouped DAPs into various medication groups. RESULTS: The prevalence and burden of DAPs on Duran's list showed a decreasing trend over the years. In 1999 the prevalence was 20% and the burden 0.35, in 2009 they were 22% and 0.35, respectively, and in 2019 they were 16% and 0.23, respectively. There were no differences in how the 75- and 80-year-olds used DAPs compared with those aged 85 years and older. The proportion of typical antipsychotics, benzodiazepines, hypnotics, urinary antispasmodics, and asthma/chronic obstructive pulmonary disease medications decreased, whereas the proportion of atypical antipsychotics, antidepressants, strong opioids, and antihistamines increased. In particular the use of mirtazapine increased-to 3.9% in 2019. In 2019 the three most prevalent groups of DAPs were antidepressants (7.4%), opioids (2.7%), and antihistamines (2.4%). CONCLUSIONS: The decrease in the use of DAPs on Duran's list is a welcome change. Although the use of old, strong DAPs has decreased, new DAPs have simultaneously emerged. Physicians need continuous education in prescribing DAPs and more recent information on the use and effects of DAPs is needed in order to decrease their exposure among the rapidly growing older population.

Plasma ceramides independently predict all-cause mortality in men aged 85.

BACKGROUND: assessing cardiovascular and mortality risk with conventional biomarkers is challenging in oldest-old due to multimorbidity and polypharmacy. Ceramides are bioactive lipids shown to predict mortality in late middle-aged cohorts. OBJECTIVE: to assess whether plasma ceramides have independent prognostic value for mortality among oldest-old (85+). DESIGN: longitudinal cohort study (Helsinki Businessmen Study, HBS) with a 3.5-year follow-up. SETTING AND SUBJECTS: survivors of HBS (125 men born in 1919-1934) visited the clinic for laboratory and clinical examination. METHODS: functional status including physical (short physical performance battery) and Montreal Cognitive Assessment (MoCA) cognitive performance was assessed and laboratory examinations included a large set of biomarkers. Plasma ceramide concentration (Cer(d18:1/16:0)) was measured using a targeted liquid chromatography-tandem mass spectrometry assay. Mortality was retrieved from national registers. RESULTS: median age was 88 years, two-thirds had multimorbidity and 59% were on statin treatment. During the follow-up, 22 (18%) men died. In a model adjusted for variables associated with mortality in the whole cohort at P < 0.20 (log glucose, SPPB, MoCA and statin use), Cer(d18:1/16:0) as a continuous trait was associated with increased mortality: hazard ratio (HR) per 1 SD 1.64 (95% confidence interval [CI] 1.23-2.18). Compared with the bottom tertile of Cer(d18:1/16:0), HR of mortality was 5.44-fold (95% CI 1.17-25.3) in the top tertile. CONCLUSIONS: these data raise the hypothesis that plasma ceramide concentrations and especially Cer(d18:1/1:60) may offer a clinically useful biomarker to evaluate prognosis in very old age. Such biomarkers are needed for geriatrics, where multimorbidity and pharmacotherapies, such as statins are prevalent hampering assessment of prognosis using conventional methods.

Benefits and limitations of statin use in primary cardiovascular prevention: recent advances.

The status of low­density lipoprotein (LDL) cholesterol is strong as an essential cause of atherosclerotic vascular disease (ASCVD) and primary target of lipid lowering. Drugs affecting primarily LDL choles-terol through an increase of LDL receptor expression are the backbone of current therapy, and generic statins are generally safe, effective, and inexpensive drugs serving this purpose. Statins are indicated for practically all patients in secondary prevention, whereas treatment in primary prevention (healthy individuals) is based on a calculated 10­year risk of ASCVD. At "borderline" (from 5% to <7.5%) and "intermediate" (from 7.5% to <20%) risk various biomarkers (eg, coronary artery calcium) are available for accurate assessment of the individual risk. The calculation of a lifetime risk instead of the 10­year risk can be especially useful in younger people. More information about the benefits and risks of statins in primary prevention in older people (>70 years of age) will be provided by ongoing randomized and controlled trials (STAREE and PREVENTABLE). In this narrative review, I shall present recent advances in the use of statins in younger and older healthy people, and discuss their benefits and potential risks. I also raise a question whether with the current evidence base, most people in affluent societies would benefit from taking statins.

Clinical trials in older people.

Randomised controlled trials (RCTs) usually provide the best evidence for treatments and management. Historically, older people have often been excluded from clinical medication trials due to age, multimorbidity and disabilities. The situation is improving, but still the external validity of many trials may be questioned. Individuals participating in trials are generally less complex than many patients seen in geriatric clinics. Recruitment and retention of older participants are particular challenges in clinical trials. Multiple channels are needed for successful recruitment, and especially individuals experiencing frailty, multimorbidity and disabilities require support to participate. Cognitive decline is common, and often proxies are needed to sign informed consent forms. Older people may fall ill or become tired during the trial, and therefore, special support and empathic study personnel are necessary for the successful retention of participants. Besides the risk of participants dropping out, several other pitfalls may result in underestimating or overestimating the intervention effects. In nonpharmacological trials, imperfect blinding is often unavoidable. Interventions must be designed intensively and be long enough to reveal differences between the intervention and control groups, as control participants must still receive the best normal care available. Outcome measures should be relevant to older people, sensitive to change and targeted to the specific population in the trial. Missing values in measurements are common and should be accounted for when designing the trial. Despite the obstacles, RCTs in geriatrics must be promoted. Reliable evidence is needed for the successful treatment, management and care of older people.

Dietary fat intake and quality in long-term care residents in two cohorts assessed 10 years apart.

PURPOSE: To describe and compare detailed dietary fat intake, fat quality and associative factors between two measuring points 10 years apart of residents living in long-term care facilities, and to reflect how fat composition and fat quality corresponds to current nutrition recommendations. METHODS: In 2007 long-term care residents (n = 374) of 25 assisted-living facilities and nursing homes and in 2017-18 long-term care residents (n = 486) of 17 respective facilities in Helsinki metropolitan area were recruited for this study. Information on the residents' heights, demographic information and use of calcium and vitamin D supplementation were retrieved from medical records. Residents' clinical assessment included Clinical Dementia Rating (CDR), the Mini Nutritional Assessment (MNA) and questionnaire related to nutrition care. Participants' energy and fat intake were determined from 1--2-day food diaries kept by the ward nurses, and fat quality indicators calculated. RESULTS: Age, gender distribution, MNA score or body mass index did not differ between the two cohorts. Residents' cognitive status, subjective health and mobility were poorer in 2017 compared to 2007. Total fat and saturated fatty acid (SFA) intakes were higher and fat quality indicators lower in the 2017 cohort residents than in the 2007 cohort residents. Sugar intake, male gender, eating independently, eating larger amounts and not having dry mouth predicted higher SFA intake in the 2017 cohort. CONCLUSIONS: The fat quality in long-term care residents in our study worsened in spite of official recommendations between the two measurement points.

Retirement as a predictor of physical functioning trajectories among older businessmen.

BACKGROUND: Associations between retirement characteristics and consequent physical functioning (PF) are poorly understood, particularly in higher socioeconomic groups, where postponing retirement has had both positive and negative implications for PF. METHODS: Multiple assessments of PF, the first of which at the mean age of 73.3 years, were performed on 1709 men who were retired business executives and managers, using the RAND-36/SF-36 instrument, between 2000 and 2010. Questionnaire data on retirement age and type of pension was gathered in 2000. Five distinct PF trajectories were created using latent growth mixture modelling. Mortality- and covariate-adjusted multinomial regression models were used to estimate multinomial Odds Ratios (mOR) on the association between retirement characteristics and PF trajectories. RESULTS: A one-year increase in retirement age was associated with decreased likelihood of being classified in the 'consistently low' (fully adjusted mOR = 0.82; 95%CI = 0.70, 0.97; P = 0.007), 'intermediate and declining' (mOR = 0.89; 95%CI = 0.83, 0.96; P = 0.002), and 'high and declining' (mOR = 0.92; 95%CI = 0.87, 0.98; P = 0.006) trajectories, relative to the 'intact' PF trajectory. Compared to old age pensioners, disability pensioners were more likely to be classified in the 'consistently low' (mOR = 23.77; 95% CI 2.13, 265.04; P = 0.010), 'intermediate and declining' (mOR = 8.24; 95%CI = 2.58, 26.35; P < 0.001), and 'high and declining' (mOR = 2.71; 95%CI = 1.17, 6.28; P = 0.020) PF trajectories, relative to the 'intact' PF trajectory. CONCLUSIONS: Among executives and managers, older age at retirement was associated with better trajectories of PF in old age. Compared to old age pensioners, those transitioning into disability and early old age pensions were at risk of having consistently lower PF in old age.

Association of plasma gelsolin with frailty phenotype and mortality among octogenarian community-dwelling men: a cohort study.

BACKGROUND: Biomarkers are needed for frailty, a common phenotype often associated with muscle loss in older people. Plasma gelsolin (pGSN) is a protein largely synthesized and secreted by skeletal muscle. AIMS: To investigate whether pGSN could be a biomarker of the frailty phenotype and predict mortality. METHODS: A homogenous cohort of males (born 1919-1934, baseline n = 3490) has been followed since the 1960s. In 2010/11, frailty phenotypes by modified Fried criteria were assessed. pGSN was measured in a convenience subset (n = 469, mean age 83) and re-measured in survivors (n = 127) in 2017. Mortality through December 31, 2018 was retrieved from national registers. Regression models were used for analyses. RESULTS: Of 469 males, 152 (32.4%) were robust, 284 (60.6%) prefrail, and 33 (7.0%) frail in 2010/11. There was a graded (p = 0.018) association between pGSN (mean 58.1 ug/mL, SD 9.3) and frailty. After multivariable adjustment, higher pGSN levels were associated with lower odds of having contemporaneous phenotypic prefrailty (OR per 1 SD 0.73, 95% CI 0.58-0.92) and frailty (OR per 1 SD 0.70, 95% CI 0.44-1.11). By 2018, 179 males (38.2%) had died, and higher baseline pGSN predicted a lower 7-year mortality rate (HR per 1 SD 0.85, 95% CI 0.72-1.00). pGSN concentrations in 2010/11 and 2017 were correlated (n = 127, r = 0.34, p < 0.001). DISCUSSION: Higher baseline pGSN concentrations were associated with a persistently robust phenotype and lower mortality rate over 7 years in a cohort of octogenarian males with high socioeconomic status and may be a promising laboratory biomarker for the development of a frailty phenotype.

Familial hypercholesterolemia and COVID-19: A menacing but treatable vasculopathic condition.

SARS-CoV-2 infection continues to cause increased morbidity and mortality, and due to the slow pace of vaccination COVID-19 will probably remain a global burden to health systems for a long time. Unfortunately, the necessary prevention and treatment strategies of COVID-19 have led to restriction measures that are hampering the routine care of common chronic metabolic conditions like hypercholesterolemia. It is of particular concern that during the acute phase of COVID-19, the control of pre-existing metabolic diseases tends to get worse which again increases the risk for complications and a poor outcome in these patients. A significant contributor to these complications is endothelial dysfunction which is associated with COVID-19. This Commentary will discuss the impact of COVID-19 on endothelial function particularly in patients with familial hypercholesterolemia (FH), a metabolic inherited disease known to in itself adversely affect endothelial function. There should be no hesitation to continue with statin therapy in severe hypercholesterolemic patients with COVID-19. We argue that in FH patients with COVID-19 the clinicians need even consider intensifying statin therapy as well as the addition of other lipid-lowering agents, such as proprotein convertase subtilisin/kexin type 9(PCSK9) inhibitors. In contrast to statins, the PCSK9 inhibitors lower lipoprotein(a) [Lp(a)] level, and, accordingly, these latter drugs need to be considered particularly in FH patients with an elevated level of Lp(a). This call applies to the in-hospital stay and also beyond. When considering that the vasculopathic effects of COVID-19 may persist, a long-term follow-up of individualized therapies in FH patients is warranted.