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Abstract On March 19, 2008 a Symposium on Pathophysiology of Ageing and Age-Related Diseases was held in Palermo, Italy. The lecture of D. Mari on Hemostasis and ageing is summarized herein. Physiological ageing is associated with increased plasma levels of many proteins of blood coagulation together with fibrinolysis impairment. This may be of great concern in view of the known association between vascular and thromboembolic diseases and ageing. On the other hand, centenarians are characterized by a state of hypercoagulability and possession of several high-risk alleles and well-known atherothrombotic risk markers but this appears to be compatible with longevity and/or health. Parameters considered risk factors for atherosclerotic vascular diseases in young people may lose their biological significance in advanced age and assume a different role.

Pain and frailty are closely linked. Chronic pain is a risk factor for frailty, and frailty is a risk factor for pain. People living with frailty also commonly have cognitive impairment, which can make assessment of pain and monitoring of pain management even more difficult. Pain may be sub-optimally treated in people living with frailty, people living with cognitive impairment and those with both these factors. Reasons for sub-optimal treatment in these groups are pharmacological (increased drug side effects, drug-drug interactions, polypharmacy), non-pharmacological (erroneous beliefs about pain, ageism, bidirectional communication challenges), logistical (difficulty in accessing primary care practitioners and unaffordable cost of drugs), and, particularly in cognitive impairment, related to communication difficulties. Thorough assessment and characterisation of pain, related sensations, and their functional, emotional, and behavioural consequences ("phenotyping") may help to enhance the assessment of pain, particularly in people with frailty and cognitive impairment, as this may help to identify who is most likely to respond to certain types of treatment. This paper discusses the potential role of "digital phenotyping" in the assessment and management of pain in people with frailty. Digital phenotyping is concerned with observable characteristics in digital form, such as those obtained from sensing-capable devices, and may provide novel and more informative data than existing clinical approaches regarding how pain manifests and how treatment strategies affect it. The processing of extensive digital and usual data may require powerful algorithms, but processing these data could lead to a better understanding of who is most likely to benefit from specific and targeted treatments., (© 2024. The Author(s).)

Purpose: To investigate the longitudinal associations between pain and depressive symptoms in adults., Methods: Prospective cohort study on data from 28,515 community-dwelling adults ≥ 50 years, free from depression at baseline (Wave 5), with follow-up in Wave 6 of the Survey of Health, Ageing and Retirement in Europe (SHARE). Significant depressive symptoms were defined by a EURO-D score ≥ 4. The longitudinal association between baseline pain intensity and significant depressive symptoms at follow-up was analysed using logistic regression models; odds ratios (ORs) and confidence intervals (CI) were calculated, adjusting for socio-demographic and clinical factors, physical inactivity, loneliness, mobility and functional impairments., Results: Mean age was 65.4 years (standard deviation 9.0, range 50-99); 14,360 (50.4%) participants were women. Mean follow-up was 23.4 (standard deviation 3.4) months. At baseline, 2803 (9.8%) participants reported mild pain, 5253 (18.4%) moderate pain and 1431 (5.0%) severe pain. At follow-up, 3868 (13.6%) participants-1451 (10.3%) men and 2417 (16.8%) women-reported significant depressive symptoms. After adjustment, mild, moderate and severe baseline pain, versus no pain, were associated with an increased likelihood of significant depressive symptoms at follow-up: ORs (95% CI) were 1.20 (1.06-1.35), 1.32 (1.20-1.46) and 1.39 (1.19-1.63), respectively. These associations were more pronounced in men compared to women, and consistent in participants aged 50-64 years, those without mobility or functional impairment, and those without loneliness at baseline., Conclusion: Higher baseline pain intensity was longitudinally associated with a greater risk of significant depressive symptoms at 2-year follow-up, in community-dwelling adults without baseline depression., (© 2023. The Author(s).)

Pain is common in people with dementia, and pain can exacerbate the behavioural and psychological symptoms of dementia. Effective pain management is challenging, not least in people with dementia. Impairments of cognition, communication and abstract thought can make communicating pain unreliable or impossible. It is unclear which biopsychosocial interventions for pain management are effective in people with dementia, and which interventions for behavioural and psychological symptoms of dementia are effective in people with pain. The result is that drugs, physical therapies and psychological therapies might be either underused or overused. People with dementia and pain could be helped by assessment processes that characterise an individual's pain experience and dementia behaviours in a mechanistic manner, phenotyping. Chronic pain management has moved from a 'one size fits all' approach, towards personalised medicine, where interventions recommended for an individual depend upon the key mechanisms underlying their pain, and the relative values they place on benefits and adverse effects. Mechanistic phenotyping through careful personalised evaluation would define the mechanisms driving pain and dementia behaviours in an individual, enabling the formulation of a personalised intervention strategy. Central pain processing mechanisms are particularly likely to be important in people with pain and dementia, and interventions to accommodate and address these may be particularly helpful, not only to relieve pain but also the symptoms of dementia., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: To investigate the longitudinal associations between pain and falls risks in adults., Methods: Prospective cohort study on data from 40,636 community-dwelling adults ≥ 50 years assessed in Wave 5 and 6 in the Survey of Health, Ageing and Retirement in Europe (SHARE). Socio-demographic and clinical information was collected at baseline (Wave 5). At 2-year follow-up (Wave 6), falls in the previous 6 months were recorded. The longitudinal associations between pain intensity, number of pain sites and pain in specific anatomic sites, respectively, and falls risk were analysed by binary logistic regression models; odds ratios (95% confidence intervals) were calculated. All analyses were adjusted for socio-demographic and clinical factors and stratified by sex., Results: Mean age was 65.8 years (standard deviation 9.3; range 50-103); 22,486 (55.3%) participants were women. At follow-up, 2805 (6.9%) participants reported fall(s) in the previous 6 months. After adjustment, participants with moderate and severe pain at baseline had an increased falls risk at follow-up of 1.35 (1.21-1.51) and 1.52 (1.31-1.75), respectively, compared to those without pain (both p < 0.001); mild pain was not associated with falls risk. Associations between pain intensity and falls risk were greater at younger age (p for interaction < 0.001). Among participants with pain, pain in ≥ 2 sites or all over (multisite pain) was associated with an increased falls risk of 1.29 (1.14-1.45) compared to pain in one site (p < 0.001)., Conclusions: Moderate, severe and multisite pain were associated with an increased risk of subsequent falls in adults., (© 2022. The Author(s).)

Background: Younger and older adults attending the Emergency Department (ED) are a heterogeneous population. Longer length of ED stay is associated with adverse outcomes and may vary by age., Aims: To evaluate the associations between age and (1) clinical characteristics and (2) length of ED stay among adults attending ED., Methods: The NOttingham Cohort study in the Emergency Department (NOCED)-a retrospective cohort study-comprises new consecutive ED attendances by adults ≥ 18 years, at a secondary/tertiary care hospital, in 2019. Length of ED stay was dichotomised as < 4 and ≥ 4 h. The associations between age and length of ED stay were analysed by binary logistic regression and adjusted for socio-demographic and clinical factors including triage acuity., Results: 146,636 attendances were analysed; 75,636 (51.6%) resulted in a length of ED stay ≥ 4 h. Attendances of adults aged 65 to 74 years, 75 to 84 years and ≥ 85 years, respectively, had an increased risk (odds ratio (95% confidence interval) of length of ED stay ≥ 4 h of 1.52 (1.45-1.58), 1.65 (1.58-1.72), and 1.84 (1.75-1.93), compared to those of adults 18 to 64 years (all p < 0.001). These findings remained consistent in the subsets of attendances leading to hospital admission and those leading to discharge from ED., Discussion and Conclusion: In this real-world cohort study, older adults were more likely to have a length of ED stay ≥ 4 h, with the oldest old having the highest risk. ED target times should take into account age of attendees., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: The world's population is ageing. Therefore, every doctor should receive geriatric medicine training during their undergraduate education. This review aims to summarise recent developments in geriatric medicine that will potentially inform developments and updating of undergraduate medical curricula for geriatric content., Methods: We systematically searched the electronic databases Ovid Medline, Ovid Embase and Pubmed, from 1st January 2009 to 18th May 2021. We included studies related to (1) undergraduate medical students and (2) geriatric medicine or ageing or older adults and (3) curriculum or curriculum topics or learning objectives or competencies or teaching methods or students' attitudes and (4) published in a scientific journal. No language restrictions were applied., Results: We identified 2503 records and assessed the full texts of 393 records for eligibility with 367 records included in the thematic analysis. Six major themes emerged: curriculum, topics, teaching methods, teaching settings, medical students' skills and medical students' attitudes. New curricula focussed on minimum Geriatrics Competencies, Geriatric Psychiatry and Comprehensive Geriatric Assessment; vertical integration of Geriatric Medicine into the curriculum has been advocated. Emerging or evolving topics included delirium, pharmacotherapeutics, healthy ageing and health promotion, and Telemedicine. Teaching methods emphasised interprofessional education, senior mentor programmes and intergenerational contact, student journaling and reflective writing, simulation, clinical placements and e-learning. Nursing homes featured among new teaching settings. Communication skills, empathy and professionalism were highlighted as essential skills for interacting with older adults., Conclusion: We recommend that future undergraduate medical curricula in Geriatric Medicine should take into account recent developments described in this paper. In addition to including newly emerged topics and advances in existing topics, different teaching settings and methods should also be considered. Employing vertical integration throughout the undergraduate course can usefully supplement learning achieved in a dedicated Geriatric Medicine undergraduate course. Interprofessional education can improve understanding of the roles of other professionals and improve team-working skills. A focus on improving communication skills and empathy should particularly enable better interaction with older patients. Embedding expected levels of Geriatric competencies should ensure that medical students have acquired the skills necessary to effectively treat older patients., (© 2021. The Author(s).)

We investigated the association between perceived neighbourhood characteristics and falls in community-dwelling adults, using data from Wave 5 and 6 of the Survey of Health, Ageing and Retirement in Europe (SHARE). We included 25,467 participants aged 50 to 103 years (mean age 66.2 ± 9.6, 58.5% women), from fourteen European countries (Austria, Belgium, Czech Republic, Denmark, Estonia, France, Germany, Israel, Italy, Luxembourg, Slovenia, Spain, Sweden, Switzerland). At baseline, we recorded individual-level factors (socio-demographic, socio-economic and clinical factors), contextual-level factors (country, urban versus rural area, European region) and perceived neighbourhood characteristics (vandalism or crime, cleanliness, feeling part of neighbourhood, helpful neighbours, accessibility to services) for each participant. We recorded falls in the six months prior to the baseline and 2-year follow-up interviews. The associations between neighbourhood characteristics and falls were analysed by binary logistic regression models; odds ratios (95% confidence intervals) were calculated. Participants reporting-versus not reporting-vandalism or crime had an increased falls risk of 1.16 (1.02-1.31) at follow-up, after full adjustment; lack of cleanliness, feeling part of the neighbourhood, perceiving neighbours as helpful and difficult accessibility to services were not associated with falls. Vandalism or crime was consistently associated with increased falls risks in women, adults without functional impairment and urban areas residents. In conclusion, adverse neighbourhood environments may account for inequality in falls risk among middle-aged and older adults and could be added to fall risk stratification tools., Supplementary Information: The online version contains supplementary material available at 10.1007/s10433-022-00685-3., Competing Interests: Conflict of interestOn behalf of all authors, the corresponding author states that there is no conflict of interest., (© The Author(s), under exclusive licence to Springer Nature B.V. 2022.)

Purpose: To investigate the association between vision and hearing impairment and falls in community-dwelling adults aged ≥ 50 years., Methods: This is a prospective study on 50,986 participants assessed in Waves 6 and 7 of the Survey of Health, Ageing and Retirement in Europe. At baseline, we recorded socio-demographic data, clinical factors and self-reported vision and hearing impairment. We classified participants as having good vision and hearing, impaired vision, impaired hearing or impaired vision and hearing. We recorded falls in the six months prior to the baseline and 2-year follow-up interviews. The cross-sectional and longitudinal associations between vision and hearing impairment categories and falls were analysed by binary logistic regression models; odds ratios (OR) and 95% confidence intervals (CI) were calculated. All analyses were adjusted for socio-demographic and clinical factors., Results: Mean age was 67.1 years (range 50-102). At baseline, participants with impaired vision, impaired hearing, and impaired vision and hearing had an increased falls risk (OR (95% CI)) of 1.34 (1.22-1.49), 1.34 (1.20-1.50) and 1.67 (1.50-1.87), respectively, compared to those with good vision and hearing (all p < 0.001). At follow-up, participants with impaired vision, without or with impaired hearing, had an increased falls risk of 1.19 (1.08-1.31) and 1.33 (1.20-1.49), respectively, compared to those with good vision and hearing (both p < 0.001); hearing impairment was longitudinally associated with falls in middle-aged women., Conclusion: Vision impairment was cross-sectionally and longitudinally associated with an increased falls risk. This risk was highest in adults with dual sensory impairment., (© 2021. European Geriatric Medicine Society.)

Purpose: To investigate the longitudinal associations between body mass index (BMI) categories and falls risk in men and women., Methods: Prospective cohort study using data from 50,041 community-dwelling adults aged ≥ 50 years assessed in Wave 6 and 7 in the cross-national Survey of Health, Ageing and Retirement in Europe (SHARE). Socio-demographic and clinical factors were assessed at baseline (Wave 6). Functional impairment was defined by any limitations in activities of daily living (ADL) or instrumental ADL (IADL). Participants were classified as underweight, normal weight, overweight or obese at baseline. At 2-year follow-up (Wave 7), falls in the previous six months were recorded. The longitudinal associations between BMI categories and falls were analysed by binary logistic regression models; odds ratios (OR) and 95% confidence intervals (CI) were calculated. All analyses were adjusted for socio-demographic and clinical factors. Furthermore, analyses were stratified by sex, age and functional impairment., Results: Mean age was 67.0 years (range 50-102); 28,132 participants were women; 4057 (8.1%) participants reported falls at follow-up. Participants had an increased falls risk [OR (95% CI)] if they were underweight [1.41 (1.06-1.88), p = 0.017] or obese [1.20 (1.09-1.32), p < 0.001] compared to those with normal weight. The association of underweight and obesity with increased falls risk was consistent in participants aged ≥ 65 years. In participants with functional impairment, underweight was associated with higher falls risk [1.61 (1.09-2.40), p = 0.018], while obesity was not., Conclusion: A U-shaped relationship between BMI and falls risk was found in community-dwelling adults., (© 2021. European Geriatric Medicine Society.)

Centenarians experience successful ageing, although they still present high heterogeneity in their health status. The frailty index is a biomarker of biological age, able to capture such heterogeneity, even at extreme old age. At the same time, other biomarkers (e.g., epigenetic clocks) may be informative the biological age of the individual and potentially describe the ageing status in centenarians. In this article, we explore the relationship between epigenetic clocks and frailty index in a cohort of Italian centenarians. No association was reported, suggesting that these two approaches may describe different aspects of the same ageing process., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: To investigate the monthly and seasonal variation in adult osteoporotic fragility fractures and the association with weather., Methods: 12-year observational study of a UK Fracture Liaison Service (outpatient secondary care setting). Database analyses of the records of adult outpatients aged 50 years and older with fragility fractures. Weather data were obtained from the UK's national Meteorological Office. In the seasonality analyses, we tested for the association between months and seasons (determinants), respectively, and outpatient attendances, by analysis of variance (ANOVA) and Tukey's test. In the meteorological analyses, the determinants were mean temperature, mean daily maximum and minimum temperature, number of days of rain, total rainfall and number of days of frost, per month, respectively. We explored the association of each meteorological variable with outpatient attendances, by regression models., Results: The Fracture Liaison Service recorded 25,454 fragility fractures. We found significant monthly and seasonal variation in attendances for fractures of the: radius or ulna; humerus; ankle, foot, tibia or fibula (ANOVA, all p-values <0.05). Fractures of the radius or ulna and humerus peaked in December and winter. Fractures of the ankle, foot, tibia or fibula peaked in July, August and summer. U-shaped associations were showed between each temperature parameter and fractures. Days of frost were directly associated with fractures of the radius or ulna (p-value <0.001) and humerus (p-value 0.002)., Conclusion: Different types of fragility fractures present different seasonal patterns. Weather may modulate their seasonality and consequent healthcare utilisation., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: COVID-19 has disproportionately affected older people., Objective: The objective of this paper to investigate whether frailty is associated with all-cause mortality in older hospital inpatients, with COVID-19., Design: Cohort study., Setting: Secondary care acute hospital., Participants: Participants included are 677 consecutive inpatients aged 65 years and over., Methods: Cox proportional hazards models were used to examine the association of frailty with mortality. Frailty was assessed at baseline, according to the Clinical Frailty Scale (CFS), where higher categories indicate worse frailty. Analyses were adjusted for age, sex, deprivation, ethnicity, previous admissions and acute illness severity., Results: Six hundred and sixty-four patients were classified according to CFS. Two hundred and seventy-one died, during a mean follow-up of 34.3 days. Worse frailty at baseline was associated with increased mortality risk, even after full adjustment (P = 0.004). Patients with CFS 4 and CFS 5 had non-significant increased mortality risks, compared to those with CFS 1-3. Patients with CFS 6 had a 2.13-fold (95% CI 1.34-3.38) and those with CFS 7-9 had a 1.79-fold (95% CI 1.12-2.88) increased mortality risk, compared to those with CFS 1-3 (P = 0.001 and 0.016, respectively). Older age, male sex and acute illness severity were also associated with increased mortality risk., Conclusions: Frailty is associated with all-cause mortality risk in older inpatients with COVID-19., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

We investigated whether osteoporotic fractures declined during lockdown, among adults aged 50 years and older. We showed that fewer outpatients attended the Fracture Clinic, for non-hip fractures, during lockdown; in contrast, no change in admissions for hip fractures was observed. This could be due to fewer outdoors falls, during lockdown., Purpose: Many countries implemented a lockdown to control the spread of the COVID-19 pandemic. We explored whether outpatient attendances to the Fracture Clinic for non-hip fragility fracture and inpatient admissions for hip fracture declined during lockdown, among adults aged 50 years and older, in a large secondary care hospital., Methods: In our observational study, we analysed the records of 6681 outpatients attending the Fracture Clinic, for non-hip fragility fractures, and those of 1752 inpatients, admitted for hip fracture, during the time frames of interest. These were weeks 1st to 12th in 2020 ("prior to lockdown"), weeks 13th to 19th in 2020 ("lockdown") and corresponding periods over 2015 to 2019. We tested for differences in mean numbers (standard deviation (SD)) of outpatients and inpatients, respectively, per week, during the time frames of interest, across the years., Results: Prior to lockdown, in 2020, 63.1 (SD 12.6) outpatients per week attended the Fracture Clinic, similar to previous years (p value 0.338). During lockdown, 26.0 (SD 7.3) outpatients per week attended the Fracture Clinic, fewer than previous years (p value < 0.001); similar findings were observed in both sexes and age groups (all p values < 0.001). During lockdown, 16.1 (SD 5.6) inpatients per week were admitted for hip fracture, similar to previous years (p value 0.776)., Conclusion: During lockdown, fewer outpatients attended the Fracture Clinic, for non-hip fragility fractures, while no change in inpatient admissions for hip fracture was observed. This could reflect fewer non-hip fractures and may inform allocation of resources during pandemic.

Background: Equality of access to memory assessment services by older adults from ethnic minorities is both an ethical imperative and a public health priority., Objective: To investigate whether timeliness of access to memory assessment service differs between older people of white British and South Asian ethnicity., Design: Longitudinal cohort., Setting: Nottingham Memory Study; outpatient secondary mental healthcare., Subjects: Our cohort comprised 3654 white British and 32 South Asian older outpatients., Methods: The criterion for timely access to memory assessment service was set at 90 days from referral. Relationships between ethnicity and likelihood of timely access to memory assessment service were analysed using binary logistic regression. Analyses were adjusted for socio-demographic factors, deprivation and previous access to rapid response mental health services., Results: Among white British outpatients, 2272 people (62.2%) achieved timely access to memory assessment service. Among South Asian outpatients, fourteen people (43.8%) achieved timely access to memory assessment service. After full adjustment, South Asian outpatients had a 0.47-fold reduced likelihood of timely access, compared to white British outpatients (odds ratio 0.47, 95% confidence interval 0.23-0.95, P value = .035). The difference became non-significant when restricting analyses to outpatients reporting British nationality or English as first language. Older age, lower index of deprivation and previous access to rapid response mental health services were associated with reduced likelihood of timely access, while gender was not., Conclusions: In a UK mental healthcare service, older South Asian outpatients are less likely to access dementia diagnostic services in a timely way, compared to white British outpatients., (© 2020 John Wiley & Sons Ltd.)

Background: Thresholds of optimal thyroid status in old age are controversial. We investigated the longitudinal association between thyroid parameters and 10-year all-cause mortality risk in older outpatients with normal thyrotropin (TSH) and modification by sex and age., Methods: Baseline TSH, free thyroxine (fT4), and free triiodothyronine (fT3) were assessed in the Milan Geriatrics 75+ Cohort Study. 324 men and 609 women older than 75 years had normal TSH. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for the associations between thyroid parameters and mortality risk using Cox regression. Sex-stratified analyses were adjusted for sociodemographic factors and comorbidities., Results: 233 men and 367 women died during follow-up. After adjustment, each 1-mU/L higher TSH was associated with decreased mortality risk in men (HR 0.83, 95% CI 0.69-0.98), but not in women (HR 1.09, 95% CI 0.95-1.24) (p for sex interaction = .006). Each 1-ng/L higher fT4 was associated with increased mortality risk in men (HR 1.11, 95% CI 1.02-1.22), but not in women (HR 0.98, 95% CI 0.93-1.04) (p for sex interaction = .013). Each 1-pg/mL higher fT3 was associated with decreased mortality risk in women (HR 0.77, 95% CI 0.60-0.98), but not in men (HR 0.80, 95% CI 0.57-1.13). The inverse association between TSH and mortality was most pronounced in men older than 85 years., Conclusions: Among older outpatients with normal TSH, higher TSH and lower fT4 were associated with decreased mortality risk in men but not in women. When assessing thyroid status, sex and age should be taken into account., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Higher blood pressure variability (BPV), independent of mean blood pressure (BP), has been associated with adverse health outcomes. We investigated the association between visit-to-visit BPV and functional decline in older adults at high cardiovascular risk., Methods: In PROspective Study of Pravastatin in the Elderly at Risk, 4745 participants with mean age of 75.2 years and high cardiovascular risk were followed for a mean of 3.2 years. BP was measured in every 3 months during the first 18 months. BPV was defined as the intraindividual SD of measurements across these visits. Functional status in basic and instrumental activities of daily living was measured using the Barthel (ADL) and Lawton (IADL) scales, first at 18 months and then during follow-up until 48 months. Functional decline was calculated over this period., Results: BPV was not cross-sectionally associated with functional status at 18 months. Higher SBPV was associated with steeper functional decline, whereas DBPV was not. Each 10 mmHg higher SBPV was associated with a 0.064 (95% confidence interval 0.016-0.112, P = 0.009) annual decline in ADL score and with a 0.078 decline (95% confidence interval 0.020-0.136, P = 0.008) in IADL score. These associations were not modified by sex, hypertension or antihypertensives. These findings were independent of mean BP, cardiovascular risk factors and morbidities and cognition., Conclusion: Higher visit-to-visit SBPV but not DBPV was associated with steeper functional decline in older adults at high cardiovascular risk. Higher SBPV is a novel risk factor for functional decline.

Background: Optimal blood pressure targets in older adults are controversial., Objective: to investigate whether the relation of blood pressure with mortality in older adults varies by age, functional and cognitive status., Design: longitudinal geriatric outpatient cohort., Setting: Milan Geriatrics 75+ Cohort Study., Subjects: One thousand five hundred and eighty-seven outpatients aged 75 years and over., Methods: The relations of systolic (SBP) and diastolic blood pressure (DBP) with mortality risk were analysed using Cox proportional hazards models. Blood pressure, Mini-Mental State Examination (MMSE) and Basic Activities of Daily Living (ADL) were assessed at baseline. All analyses were adjusted for socio-demographic factors, co-morbidities and medications., Results: One thousand and forty-six patients died during 10-year follow-up. The relationships of SBP and DBP with mortality risk were U-shaped; SBP of 165 mmHg and DBP of 85 mmHg were associated with the lowest mortality. Patients with SBP < 120 mmHg and patients with SBP 120-139 mmHg had 1.64-fold (95% confidence intervals, CI 1.21-2.23) and 1.32-fold (95% CI 1.10-1.60) higher mortality risk than patients with SBP 160-179 mmHg (P values 0.001 and 0.004, respectively). In patients with SBP below 180 mmHg, higher SBP was associated with lower mortality in patients with impaired ADL and MMSE but not in those with preserved ADL and/or MMSE (P for interaction 0.033). Age did not modify the correlation of SBP with mortality., Conclusions: The correlations of SBP and DBP with mortality were U-shaped. Higher SBP is related to lower mortality in subjects with impaired ADL and MMSE. ADL and MMSE may identify older subjects who benefit from higher blood pressure., (© The Author 2015. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Heart rate and heart rate variability, markers of cardiac autonomic function, have been linked with cardiovascular disease. We investigated whether heart rate and heart rate variability are associated with functional status in older adults, independent of cardiovascular disease., Methods: We obtained data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). A total of 5042 participants were included in the present study, and mean follow-up was 3.2 years. Heart rate and heart rate variability were derived from baseline 10-second electrocardiograms. Heart rate variability was defined as the standard deviation of normal-to-normal RR intervals (SDNN). Functional status in basic (ADL) and instrumental (IADL) activities of daily living was measured using Barthel and Lawton scales, at baseline and during follow-up., Results: The mean age of the study population was 75.3 years. At baseline, higher heart rate was associated with worse ADL and IADL, and lower SDNN was related to worse IADL (all p values < 0.05). Participants in the highest tertile of heart rate (range 71-117 beats/min) had a 1.79-fold (95% confidence interval [CI] 1.45-2.22) and 1.35-fold (95% CI 1.12-1.63) higher risk of decline in ADL and IADL, respectively (p for trend < 0.001 and 0.001, respectively). Participants in the lowest tertile of SDNN (range 1.70-13.30 ms) had 1.21-fold (95% CI 1.00-1.46) and 1.25-fold (95% CI 1.05-1.48) higher risk of decline in ADL and IADL, respectively (both p for trends < 0.05). All associations were independent of sex, medications, cardiovascular risk factors and comorbidities., Interpretation: Higher resting heart rate and lower heart rate variability were associated with worse functional status and with higher risk of future functional decline in older adults, independent of cardiovascular disease. This study provides insight into the role of cardiac autonomic function in the development of functional decline., (© 2015 Canadian Medical Association or its licensors.)

Objectives: To evaluate whether the relationship between blood pressure (BP) measures and cognitive function is different according to age and functional status in older outpatients., Design: Cross-sectional., Setting: Outpatient hospital-based Milan Geriatrics 75+ Cohort Study., Participants: Individuals aged 75 and older (N = 1,540)., Measurements: Blood pressure, Mini-Mental State Examination (MMSE), basic activities of daily living (ADLs), and instrumental activities of daily living (IADLs) were assessed. Associations between BP measures and MMSE score were first analyzed in the total population using linear regression models and were then further examined according to strata of age, ADLs, and IADLs. All analyses were adjusted for sociodemographic factors and presence of comorbidities., Results: In the total population, higher systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP), and mean arterial pressure (MAP) were all associated with higher MMSE score (all P < .05). Each 10-mmHg higher SBP and DBP was associated with a 0.26- and 0.55-point higher MMSE score, respectively. The associations between MMSE score and SBP, DBP, and MAP differed materially according to strata of age and functioning and were most pronounced in those aged 85 and older, with ADL impairments, and with IADL impairments., Conclusion: Higher BP is associated with better cognitive function in the oldest old and in those with impaired functional status., (© 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.)

Centenarians and their offspring are increasingly considered a useful model to study and characterize the mechanisms underlying healthy aging and longevity. The aim of this project is to compare the prevalence of age-related diseases and telomere length (TL), a marker of biological age and mortality, across five groups of subjects: semisupercentenarians (SSCENT) (105-109years old), centenarians (CENT) (100-104years old), centenarians' offspring (CO), age- and gender-matched offspring of parents who both died at an age in line with life expectancy (CT) and age- and gender-matched offspring of both non-long-lived parents (NLO). Information was collected on lifestyle, past and current diseases, medical history and medication use. SSCENT displayed a lower prevalence of acute myocardial infarction (p=0.027), angina (p=0.016) and depression (p=0.021) relative to CENT. CO appeared to be healthier compared to CT who, in turn, displayed a lower prevalence of both arrhythmia (p=0.034) and hypertension (p=0.046) than NLO, characterized by the lowest parental longevity. Interestingly, CO and SSCENT exhibited the longest (p<0.001) and the shortest (p<0.001) telomeres respectively while CENT showed no difference in TL compared to the younger CT and NLO. Our results strengthen the hypothesis that the longevity of parents may influence the health status of their offspring. Moreover, our data also suggest that both CENT and their offspring may be characterized by a better TL maintenance which, in turn, may contribute to their longevity and healthy aging. The observation that SSCENT showed considerable shorter telomeres compared to CENT may suggest a progressive impairment of TL maintenance mechanisms over the transition from centenarian to semisupercentenarian age., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The role of epigenetics in the modulation of longevity has not been studied in humans. To this aim, (1) we evaluated the DNA methylation from peripheral leukocytes of 21 female centenarians, their 21 female offspring, 21 offspring of both non-long-lived parents, and 21 young women through ELISA assay, pyrosequencing analysis of Alu sequences, and quantification of methylation in CpG repeats outside CpG islands; (2) we compared the DNA methylation profiles of these populations through Infinium array for genome-wide CpG methylation analysis. We observed an age-related decrease in global DNA methylation and a delay of this process in centenarians' offspring. Interestingly, literature data suggest a link between the loss of DNA methylation observed during aging and the development of age-associated diseases. Genome-wide methylation analysis evidenced DNA methylation profiles specific for aging and longevity: (1) aging-associated DNA hypermethylation occurs predominantly in genes involved in the development of anatomical structures, organs, and multicellular organisms and in the regulation of transcription; (2) genes involved in nucleotide biosynthesis, metabolism, and control of signal transmission are differently methylated between centenarians' offspring and offspring of both non-long-lived parents, hypothesizing a role for these genes in human longevity. Our results suggest that a better preservation of DNA methylation status, a slower cell growing/metabolism, and a better control in signal transmission through epigenetic mechanisms may be involved in the process of human longevity. These data fit well with the observations related to the beneficial effects of mild hypothyroidism and insulin-like growth factor I system impairment on the modulation of human lifespan.

Longevity phenotype in humans results from the influence of environmental and genetic factors. Few gene polymorphisms have been identified so far with a modest effect on lifespan leaving room for the search of other players in the longevity game. It has been recently demonstrated that targeted disruption of the mouse homolog of the human angiotensin II type 1 receptor (AT1R) gene (AGTR1) translates into marked prolongation of animal lifespan (Benigni et al., J Clin Invest 119(3):524-530, 2009). Based on the above study in mice, here we sought to search for AGTR1 variations associated to reduced AT1 receptor protein levels and to prolonged lifespan in humans. AGTR1 was sequenced in 173 Italian centenarians and 376 younger controls. A novel non-synonymous mutation was detected in a centenarian. Two polymorphisms in AGTR1 promoter, rs422858 and rs275653, in complete linkage disequilibrium, were significantly associated with the ability to attain extreme old age. We then replicated the study of rs275653 in a large independent cohort of Japanese origin (598 centenarians and semi-supercentenarians, 422 younger controls) and indeed confirmed its association with exceptional old age. In combined analyses, rs275653 was associated to extreme longevity either at recessive model (P = 0.007, odds ratio (OR) 3.57) or at genotype level (P = 0.015). Significance was maintained after correcting for confounding factors. Fluorescence activated cell sorting analysis revealed that subjects homozygous for the minor allele of rs275653 had less AT1R-positive peripheral blood polymorphonuclear cells. Moreover, rs275653 was associated to lower blood pressure in centenarians. These findings highlight the role of AGTR1 as a possible candidate among longevity-enabling genes.

Factor structure analyses have revealed the presence of specific biological system markers in healthy humans and diseases. However, this type of approach in very old persons and in type 2 diabetes (T2DM) is lacking. A total sample of 2,137 Italians consisted of two groups: 1,604 healthy and 533 with T2DM. Age (years) was categorized as adults (≤65), old (66-85), oldest old (>85-98) and centenarians (≥99). Specific biomarkers of routine haematological and biochemical testing were tested across each age group. Exploratory factorial analysis (EFA) by principal component method with Varimax rotation was used to identify factors including related variables. Structural equation modelling (SEM) was applied to confirm factor solutions for each age group. EFA and SEM identified specific factor structures according to age in both groups. An age-associated reduction of factor structure was observed from adults to oldest old in the healthy group (explained variance 60.4% vs 50.3%) and from adults to old in the T2DM group (explained variance 57.4% vs 44.2%). Centenarians showed three-factor structure similar to those of adults (explained variance 58.4%). The inflammatory component became the major factor in old group and was the first one in T2DM. SEM analysis in healthy subjects suggested that the glucose levels had an important role in the oldest old. Factorial structure change during healthy ageing was associated with a decrease in complexity but showed an increase in variability and inflammation. Structural relationship changes observed in healthy subjects appeared earlier in diabetic patients and later in centenarians.

Unlabelled: Centenarians' offspring represent a suitable model to study age-dependent variables (e.g. IGF-I) potentially involved in the modulation of the lifespan. The aim of the present study was to investigate the role of the IGF-I in human longevity. We evaluated circulating IGF-I bioactivity measured by an innovative IGF-I Kinase Receptor Activation (KIRA) Assay, total IGF-I, IGFBP-3, total IGF-II, insulin, glucose, HOMA2-B% and HOMA2-S% in 192 centenarians' offspring and 80 offspring-controls of which both parents died relatively young. Both groups were well-matched for age, gender and BMI with the centenarians' offspring. IGF-I bioactivity (p〈0.01), total IGF-I (p〈0.01) and the IGF-I/IGFBP-3 molar ratio (p〈0.001) were significantly lower in centenarians' offspring compared to offspring matched-controls. Serum insulin, glucose, HOMA2-B% and HOMA2-S% values were similar between both groups. In centenarians' offspring IGF-I bioactivity was inversely associated to insulin sensitivity., In Conclusion: 1) centenarians' offspring had relatively lower circulating IGF-I bioactivity compared to offspring matched-controls; 2) IGF-I bioactivity in centenarians' offspring was inversely related to insulin sensitivity. These data support a role of the IGF-I/insulin system in the modulation of human aging process.

Adipose tissue seems to be a pivotal organ in the aging process. We investigated whether healthy aging could have its roots in a sound metabolic condition from the first year of life by evaluating leptin and adiponectin levels in neonates [33 adequate for gestational age (AGA) and 29 small for gestational age (SGA)], 48 centenarians, and 50 healthy elderly subjects. At birth, SGA neonates showed lower leptin levels (SGA 0.88 +/- 0.28; AGA 2.22 +/- 0.91 ng/mL; p < 0.05) and comparable adiponectin levels with respect to AGA. At 1 year, SGA showed increased leptin (SGA 1.74 +/- 0.28; AGA 1.31 +/- 0.19 ng/mL) and slightly reduced adiponectin concentrations (SGA 35.51 +/- 2.53; AGA 38.56 +/- 3.18 microg/mL) than AGA. Centenarians showed lower leptin (centenarians 18.71 +/- 3.78; elderly 34.81 +/- 7.27 ng/mL; p < 0.05) and higher adiponectin levels (centenarians 55.63 +/- 7.7; elderly 33.51 +/- 4.1 microg/mL; p < 0.05) than elderly subjects. Centenarians, like AGA infants during the first year of life, show a favorable adipokine profile, suggesting that the metabolic condition at early age could affect the longevity of an individual.