The aim of this study was to evaluate the effect of growth hormone (GH) deficiency in primordial follicle reserve, DNA damage and macrophage infiltration in the ovaries of young mice. Ovaries from six-month-old GH-deficient Ames Dwarf (df/df) and Normal (N/df) mice were used. The number of primordial follicles was higher in df/df mice (p = 0.0026). Also, df/df mice had a lower number of primary (p = 0.023), secondary (p = 0.0052) and tertiary (p = 0.019) follicles. These findings indicate a slower rate of primordial follicle activation in df/df mice. Female df/df mice had decreased γH2AX foci intensity in oocytes of primordial (p = 0.015) and primary (p = 0.0004) follicles compared to N/df mice. Also, df/df mice had reduced γH2AX intensity in granulosa cells of primordial (p = 0.0002) and primary (p < 0.0001) follicles. Overall, this indicate to us that df/df mice accumulate less DNA damage in the ovarian reserve compared to N/df mice. Additionally, macrophage infiltration was also reduced in ovaries of df/df mice compared to N/df mice (p = 0.033). Interestingly, df/df mice had a reduced number of granulosa cells around primordial (p = 0.0024) and primary (p = 0.007) follicles compared to N/df mice. Also, df/df mice had a small diameter of primordial follicle nuclei (p = 0.0093), secondary follicle oocyte (p = 0.046) and tertiary follicle (p = 0.012). This points to the role of granulosa cell proliferation and oocyte growth for primordial follicle activation. The current study points to the role of the GH/IGF-I axis in extending lifespan of reproductive health, along with maintenance of oocyte DNA integrity and reduced ovarian inflammation.

Background Even though increasing attention is given to deprescribing owing to the risks related to polypharmacy in older adults, deprescribing is not yet part of clinical culture. Methods We conducted three focus groups with 25 internists, geriatricians and general practitioners to explore the factors influencing the implementation of deprescribing in the Italian context, and more specifically: i. to investigate the barriers to deprescribing; ii. to define strategies and actions to address these barriers; and iii. to identify skills and tools that may assist in implementing deprescribing in clinical practice. Thematic analysis was used. Results Six themes were identified: Good reasons for deprescribing, Difficulties and doubts about deprescribing, System factors affecting polypharmacy and deprescribing, Perspectives on how to practically approach polypharmacy, Need for effective communication with patients and caregivers, Taking responsibility and starting action. Participants reported a willingness to challenge themselves by addressing the barriers to deprescribing through regular review of prescriptions and collaboration with colleagues and patients. Conclusions Italian internists, geriatricians and general practitioners reported many system-level barriers to deprescribing as well as some doubts about its necessity. Strategies to address the barriers to deprescribing include regular medication review and enhancing collaboration with colleagues and patients. Additionally, participants were willing to challenge themselves and use uncertainty as an impetus for deprescribing.

Introduction Non-motor symptoms such as cognitive and gastrointestinal (GI) symptoms are common in Parkinson's disease (PD). In PD, GI-symptoms often present prior to motor symptoms. It is hypothesized that GI-symptoms reflect disruptions of the microbiome-gut-brain axis, which leads to altered immune functioning, chronic neuroinflammation, and subsequent neurodegeneration. Initial evidence links gut-dysbiosis to PD pathology and motor symptom severity. The present study examines the longitudinal relationship between severity of GI-symptoms and cognitive impairment in newly diagnosed PD patients. Methods A secondary data analysis of the Parkinson's Progression Markers Initiative (PPMI) included 423 newly diagnosed PD patients who were followed for up to 5 years. Participants underwent neuropsychological tests of processing speed, attention, visuospatial functioning, verbal learning and verbal delayed recall. Participant were classified as cognitive intact, mild cognitive impairment or Parkinson's disease dementia. Frequency of GI-symptoms were assessed with the Scales for Outcomes in Parkinson's Disease Autonomic (SCOPA-AUT). Multi-level models (MLM) examined the longitudinal relationship between GI symptoms and cognitive impairment. Results All cognitive outcomes were predicted by the main effect of GI symptoms, or the GI-symptom X Occasion interaction term. Specifically, more severe GI-symptoms were predictive of a less favorable trajectory of performance on tests of letter fluency, visuospatial, learning and memory. Cognitive performance was uniquely associated with GI-symptoms and unrelated to non-GI autonomic symptoms. Conclusions The presence of GI symptoms may serve as an early marker of cognitive impairment in PD. Future studies should examine specific mechanisms underlying the relationship between gut-dysbiosis and cognitive impairment.

Physical activity may reduce cancer initiation. High-intensity interval training (HIT) has been reported to be superior to moderate continuous endurance training (ET) for maximizing health outcomes in cardiovascular disease, obesity and type 2 diabetes. However, the role of HIT vs. ET in the prevention of liver cancer is poorly understood. This study aimed to determine how HIT vs. ET affects cancer initiation in mice with the hepatocellular carcinogen diethylnitrosamine (DEN). C57BL/6 mice were treated with DEN at 3–12 weeks of age and, from 8 to 26 weeks of age, treated with either of exercise modes on treadmill: HIT (85–90% VO2max with intervals) and ET (65–75% VO2max without intervals). We found that mice treated with ET had lower cancer initiation but higher fat mass compared to control DEN-injected mice. In contrast, HIT could not significantly reduce cancer initiation and tumor volumes. Metabolomic analysis in the liver indicated marked differences in cholesterol, palmitic acid, stearic acid, uracil, hydroxypyridine and maltose between HIT- and ET-treated mice, and demonstrated good and obvious separation between ET and DEN control group. Furthermore, mice treated with ET had lower expression of pro-inflammatory cytokines and pro-proliferation genes in liver compared to DEN control group. ET protocol reduced the accumulation of toxic metabolite carbamate, increased the protein level of caspase-1, and reduced JNK phosphorylation in liver. These data indicates that moderate-intensity endurance training may be superior to high-intensity interval training for reducing liver cancer initiation in mice.

BackgroundAlbuminuria is highly prevalent among older adults, especially those with diabetes. It is associated with several chronic diseases, but its overall impact on the health of older adults, as measured by hospitalization, has not been quantified. MethodsWe followed 3110 adults, mean age 78 years, for a median 9.75 years, of whom 654 (21%) had albuminuria (>30 mg albumin / gram creatinine) at baseline. Poisson regression models, adjusted for cardiovascular, renal and demographic factors, were used to evaluate association of albuminuria with all-cause and cause-specific hospitalizations, as defined by ICD, version 9, categories. ResultsThe rates of hospitalization per 100 patient-years were 65.85 for participants with albuminuria and 37.55 for participants without albuminuria. After adjustment for covariates, participants with albuminuria were more likely to be hospitalized for any cause than participants without albuminuria (incident rate ratio [IRR], 1.39 [95% confidence intervals, 1.27. 1.53] and to experience more days in hospital (IRR 1.56 [1.37, 1.76]). The association of albuminuria with hospitalization was similar among participants with and without diabetes (adjusted IRR for albuminuria vs no albuminuria: diabetes 1.37 [1.11, 1.70], no diabetes 1.40 [1.26, 1.55]; p interaction NS). Albuminuria was significantly associated with hospitalization for circulatory, endocrine, genitourinary, respiratory, and injury categories. ConclusionsAlbuminuria in older adults is associated with an increased risk of hospitalization for a broad range of illnesses. Albuminuria in the presence or absence of diabetes appears to mark a generalized vulnerability to diseases of aging among older adults.

BackgroundLow walking ability is highly prevalent with advancing age and predicts major health outcomes. Metabolomics may help to better characterize differences in walking ability among older adults, providing insight into potentially altered molecular processes underlying age-related decline in functioning. We sought to identify metabolites and metabolic pathways associated with high versus low walking ability among 120 participants ages 79-95 from the CHS All Stars study. MethodsUsing a nested case-control design, 60 randomly selected participants with low walking ability were matched one-to-one on age, gender, race, and fasting time with 60 participants with high walking ability. High versus low walking ability was defined as being in the best versus worst tertiles for both gait speed (≥0.9 versus <0.7m/s) and the Walking Ability Index (7-9 versus 0-1). Using liquid chromatography-mass spectrometry, 569 metabolites were identified in overnight-fasting plasma. ResultsNinety-six metabolites were associated with walking ability, where 24% were triacylglycerols. Triacylglycerols that were higher among those with high walking ability consisted mostly of polyunsaturated fatty acids, whereas triacylglycerols that were lower among those with high walking ability consisted mostly of saturated or monounsaturated fatty acids. Body composition partly explained associations between some metabolites and walking ability. Proline and arginine metabolism was a top pathway associated with walking ability. ConclusionThese results may partly reflect pathways of modifiable risk factors, including excess dietary lipids and lack of physical activity, contributing to obesity and further alterations in metabolic pathways that lead to age-related decline in walking ability in this older adult cohort.

In the last decade, cognitive frailty has gained great attention from the scientific community. It is characterized by high inflammation and oxidant state, endocrine and metabolic alterations, mitochondria dysfunctions and slowdown in regenerative processes and immune system, with a complex and multifactorial aetiology. Although several treatments are available, challenges regarding the efficacy and the costs persist. Here, we proposed an alternative non-pharmacological, non-side-effect, low cost therapy based on anti-inflammation, antioxidant, regenerative and anti-pathogens properties of ozone (O3), through the activation of several molecular mechanisms (Nrf2-ARE, NF-κB, NFAT, AP-1, HIFα). We highlighted how these specific processes could be implicated in cognitive frailty to identify putative therapeutic targets for its treatment. The O2-O3 therapy has never been tested for cognitive frailty. This work provides thus wide scientific background to build a consistent rationale for testing for the first time this therapy, that could modulate the immune, inflammatory, oxidant, metabolic, endocrine, microbiota and regenerative processes impaired in cognitive frailty. Although insights are needed, the O2-O3 therapy could represent a faster, easier, inexpensive monodomain intervention, working in absence of side effects, for cognitive frailty.

Stroke is a highly prevalent disease among older people and can have a major impact on daily functioning and quality of life. When community-dwelling older people are hospitalized due to stroke, discharge to an intermediate care facility for geriatric rehabilitation is indicated when return to the previous living situation is expected but not yet possible. However, a substantial proportion is still unable to return home after discharge and has to be admitted to a residential care setting. This study aims to identify which factors are associated with home discharge after inpatient rehabilitation among frail and multimorbid older stroke patients. This study is a longitudinal cohort study among 92 community-dwelling stroke patients aged 65 years or over. All patients were admitted to one of eight participating intermediate care facilities for geriatric rehabilitation, under the expectation to return home after rehabilitation. We examined whether 16 potentially relevant factors (age; sex; household situation before admission; stroke history; cardiovascular disorders; diabetes mellitus; multimorbidity; cognitive disability; neglect; apraxia; dysphagia; urinary and bowel incontinence; emotional problems; sitting balance; daily activity level; and independence in activities of daily living) measured at admission were associated with discharge to the former living situation. Logistic regression analysis was used for statistical analysis. Mean age of the patients was 79.0 years (SD 6.4) and 51.1% was female. A total of 71 patients (77.1%) were discharged to the former living situation within 6 months after the start of geriatric rehabilitation. Of the 16 factors analysed, only a higher level of independence in activities of daily living at admission was significantly associated with home discharge. Our study shows that the vast majority of previously identified factors predicting home discharge among stroke patients, could not predict home discharge among a group of frail and multimorbid older persons admitted to geriatric rehabilitation. Only a higher level of independence in activities of daily living at admission was significantly related to home discharge. Additional insight in other factors that might predict home discharge after geriatric rehabilitation among this specific group of frail older stroke patients, is needed. Trial registration: ISRCTN ISRCTN62286281. Registered 19-3-2010.

Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disorder characterized by rapidly progressive autonomic and motor dysfunction. Pathologically, MSA is mainly characterized by the abnormal accumulation of misfolded α-synuclein in the cytoplasm of oligodendrocytes, which plays a major role in the pathogenesis of the disease. Striatonigral degeneration and olivopontecerebellar atrophy underlie the motor syndrome, while degeneration of autonomic centers defines the autonomic failure in MSA. At present, there is no treatment that can halt or reverse its progression. However, over the last decade several studies in preclinical models and patients have helped to better understand the pathophysiological events underlying MSA. The etiology of this fatal disorder remains unclear and may be multifactorial, caused by a combination of factors which may serve as targets for novel therapeutic approaches. In this review, we summarize the current knowledge about the etiopathogenesis and neuropathology of MSA, its different preclinical models, and the main disease modifying therapies that have been used so far or that are planned for future clinical trials.

Following publication of the original article [1], we have been notified that acknowledgement should be added to the text of the articles. The Acknowledgement section should read as follows:

Cognitive impairment is a major health concern among older and oldest people. Moreover, stroke is a relevant contributor for cognitive decline and development of dementia. The study of cognitive decline focused on stroke as the important risk factor by recruiting older and oldest is still lagging behind. Therefore, the aim of this study was to investigate the importance of stroke as a risk factor of cognitive decline during 3 years in community dwelling older and oldest people. This study was longitudinal study with a 3-year follow-up in Japan. The participants were 1333 community dwelling older and oldest people (70 years old = 675, 80 years old = 589, and 90 years old = 69). Data collected included basic data (age, sex, and history of stroke), vascular risk factors (hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, and current smoking), and social factors (educational level, frequency of going outdoors, long-term care (LTC) service used, and residential area). The Japanese version of the Montreal Cognitive Assessment (MoCA-J) was decline of ≥2 points was defined as cognitive decline. Multiple logistic regression analysis was used to investigate the association between stroke and other risk factors with cognitive decline during a 3-year follow-up. The fit of the hypothesized model by multiple logistic regression showed that a history of stroke, advanced age, and greater MoCA-J score at the baseline were important risk factors, while the presence of dyslipidemia and a higher educational level were protective factors that were significantly correlated with cognitive decline during the 3-year follow-up. The cognitive decline after the 3-year follow-up was influenced by the history of stroke and advanced age, while greater MoCA-J score at the baseline was positively associated with subsequent 3 years cognitive decline. The protective factors were the presence of dyslipidemia and a higher educational level. Therefore, these factors are considered important and should be taken into consideration when searching for creative solutions to prevent cognitive decline after stroke in community dwelling older and oldest people.

Cell-to-cell variation in gene expression increases among homologous cells within multiple tissues during aging. We call this phenomenon variegated gene expression (VGE). Long, healthy life requires robust and coordinatedgene expression. We posit that nature may have evolved VGE as a bet-hedging mechanism to protect reproductively active populations. The price we may pay is accelerated aging. That hypothesis will require the demonstration that genetic loci are capable of modulating degrees of VGE. While loci controlling VGE in yeast and genes controlling inter-individual variation in gene expression in C. elegans have been identified, there has been no compelling evidence for the role of specific genetic loci in modulations of VGE of specific targets in humans. With the assistance of a core facility, we used a customized library of siRNA constructs to screen 1,195 human genes to identify loci contributing to the control of VGE of a gene with relevance to the biology of aging. We identified approximately 50 loci controlling VGE of the prolongevity gene, SIRT1. Because of its partial homology to FOXO3A, a variant of which is enriched in centenarians, our lab independently confirmed that the knockdown of FOXF2greatly diminished VGE of SIRT1 but had little impact upon the VGE of WRN. While the role of these VGE-altering genes on aging invivo remains to be determined, we hypothesize that some of these genes can be targeted to increase functionality during aging.

BACKGROUNDReal-life community mobility measures for older adults, especially those with Parkinson’s disease, are important tools when helping individuals maintain optimal function and quality of life. This is one of the first studies to compare an objective GPS sensor and subjective self-report community mobility measures in an older clinical population. METHODSOver 14 days, 54 people in Ontario, Canada with early to mid-stage Parkinson’s Disease (mean age = 67.5 ± 6.3 years; 47 men; 46 retired) wore a wireless inertial measurement unit with GPS (WIMU-GPS), and completed the Life Space Assessment and mobility diaries. We assessed the convergent validity, reliability and agreement on mobility outcomes using Spearman’s correlation, intraclass correlation coefficient and Bland-Altman analyses, respectively. RESULTSConvergent validity was attained by the WIMU-GPS for trip frequency (rs = 0.69, 95% CI = 0.52 to 0.81) and duration outside (rs = 0.43, 95% CI = 0.18 to 0.62), but not for life space size (rs = 0.39, 95% CI = 0.14 to 0.60). The Life Space Assessment exhibited floor and ceiling effects. Moderate agreements were observed between WIMU-GPS and diary for trip frequency and duration (intraclass correlation coefficients = 0.71, 95% CI = 0.51 to 0.82; 0.67, 95% CI = 0.42 to 0.82, respectively). Disagreement was more common among non-retired individuals. CONCLUSIONSWIMU-GPS could replace diaries for trip frequency and duration assessments in older adults with Parkinson’s Disease. Both assessments are best used for retired persons. However, the Life Space Assessment may not reflect actual mobility.

BackgroundThe ageing process is characterised by declines in physical and cognitive function. However, the relationship between these trajectories remains a topic of investigation. MethodsUsing four data waves collected triennially between ages 70 and 79, we tested for associations between multiple cognitive ability domains (verbal memory, processing speed, and visuospatial ability) and physical functions (walking speed, grip strength, and lung function). We firstly tested for associations between linear declines in physical and cognitive functions over the entire 9-year study period, and then, for lead-lag coupling effects between 3-year changes in cognitive and physical functions. ResultsSteeper linear decline in walking speed was moderately correlated with steeper linear declines in each cognitive domain. Steeper linear decline in grip strength was moderately correlated with steeper linear declines in verbal memory and processing speed. Lead-lag coupling models showed that decline in verbal memory was preceded by declines in walking speed and grip strength. By contrast, decline in grip strength was preceded by declines in processing speed and visuospatial ability, and decline in walking speed was preceded by decline in visuospatial ability. Following additional adjustment for covariates, only coupling effects from earlier decline in processing speed to later decline in grip strength remained significant (β = 0.545, p = 0.006). ConclusionOur findings provide further evidence of an association between cognitive and physical declines and point to the potential order in which these changes occur. Decline in processing speed in particular may serve as a unique early marker of declining upper body strength.

BackgroundKnowledge of decision-making preference of patients and caregivers is needed to facilitate deprescribing. This study aimed to assess the perspectives of caregivers and older adults towards deprescribing in an Asian population. Secondary objectives were to identify and compare characteristics associated with these attitudes and beliefs. MethodsA cross-sectional survey of two groups of participants was conducted using the Revised Patients’ Attitudes Towards Deprescribing questionnaire. Descriptive results were reported for participants’ characteristics and questionnaire responses from four factors (belief in medication inappropriateness, medication burden, concerns about stopping, and involvement) and two global questions. Correlation between participant characteristics and their responses were analyzed. ResultsA total of 1,057 (615 older adults; 442 caregivers) participants were recruited from ten institutions in Singapore. In which 511 (83.0%) older adults and 385 (87.1%) caregivers reported that they would be willing to stop one or more of their medications if their doctor said it was possible, especially among older adults recruited from acute-care hospitals (85.3%) compared to older adults in community pharmacies (73.6%). Individuals who take more than 5 medications and those with higher education were correlated with greater agreement in inappropriateness and involvement respectively. ConclusionsClinicians should consider discussing deprescribing with older adults and caregivers in their regular clinical practice, especially when polypharmacy is present. Further research is needed into how to engage older adults and caregivers in shared decision making based on their attitudes towards deprescribing.

Introduction Advancing age is a major risk factor for a range of diseases such as, cardiovascular disease, diabetes, cancer and neurodegenerative diseases. In addition, over a third of the population are overweight and obesity is becoming more prevalent in younger people. Ageing and obesity are both linked to a chronic proinflammatory state and elevated oxidative stress, which have both been implicated in cardiovascular and neurodegenerative diseases. Platelets contain all the necessary machinery to process the Amyloid precursor protein AβPP, a pathway thought to be perturbed in Alzheimer's Disease (AD). The ratio of AβPP isoforms present in platelets, and the amount of alpha secretase ADAM10, that works to process AβPP, appear to be associated with cognitive decline and a diagnosis of Alzheimer's disease. The aim of this study was to assess changes in AβPP ratio, ADAM10 and markers of inflammation and oxidative stress with ageing and obesity. Materials and methods Ninety participants were recruited to this study to provide one blood sample. Platelet-rich plasma and platelet lysates were collected and the expression of AβPPr, proADAM10 and mADAM10 was assessed by Western blotting. In addition, markers of inflammation (IL-6) and oxidative stress (8-Isoprostane) were assessed in plasma. Results Participants were placed into one of four groups based on their age and body mass index (Young/Lean, Young/obese, Old/Lean and Old/Obese). IL-6 was able to significantly distinguish obese from lean participants (AUC of 0.80, SE = 0.05, P < 0.001). Plasma isoprostanes were able to distinguish between both young/old (AUC of 0.73, SE = 0.05, P < 0.01), and obese/non-obese participants (AUC of 0.66, SE = 0.01, P < 0.01). Plasma protein carbonyls could distinguish young and old participants (AUC of 0.69, SE = 0.07 P < 0.02). Old Lean participants had significantly lower mADAM10 expression than both Young Lean and Young Obese participants (p < 0.05). Old obese participants had significantly lower proADAM10 expression compared to both Young Lean and Young Obese (p < 0.05). Both mADAM10 and proADAM10 were significantly decreased with advancing age (p < 0.05). Conclusions The findings presented in this study provide evidence that blood-based biomarkers related to the pathology of AD are altered with age and obesity in otherwise healthy adults. Ageing was more strongly associated with elevated markers of oxidative stress whereas obesity was associated with elevated inflammatory IL-6.

This letter to the editor acknowledges the contribution of Akbar et al. to the field of tardive dyskinesia (TD) and provides important regulatory information about the potential for parkinson-like symptoms in patients with TD who are treated with valbenazine.

Femoral neck fractures (FNFs), which are common in the older population, are associated with high mortality and morbidity. Some 20% of FNFs are undisplaced (uFNFs). The routine surgical procedure for uFNFs is internal fixation (IF) with 2–3 screws/pins with a reported reoperation rate in older patients (age ≥ 75 years) of up to 21%. The reoperation rate for hemiarthroplasties for displaced fractures is lower than for undisplaced fractures operated with IF. This study will aim to determine whether the outcome for older patients with an uFNF can be improved by replacing the hip instead of preserving it. A national multicentre, register-based, randomised controlled trial (rRCT) will be conducted. For this trial, 1440 patients, ≥75 years with an acute uFNF, will be allocated. Eligible patients will be identified by the Swedish Fracture Register (SFR) platform, which will notify the admitting orthopaedic surgeon of eligibility. After informed consent has been given and documented, patients will be randomised to either IF (control group) or arthroplasty (intervention group) within the SFR platform. Injury mechanism, fracture classification, date of injury, and type of treatment are registered in the SFR. Type and brand of arthroplasty, surgical approach, and fixation are obtained from the Swedish Hip Arthroplasty Register (SHAR). The study cohort from the SFR will be cross-checked with the National Patient Register and the SHAR for outcome variables at 2, 5, and 10 years. The primary outcome will be a composite variable comprising reoperation rate and mortality at 2 years postoperatively. Secondary endpoints will include reoperation rate and mortality as stand-alone variables. In addition, secondary endpoints will be patient-reported outcomes as measured by the Short Musculoskeletal Functional Assessment questionnaire at 1 year postoperatively as routinely collected within the SFR. Further secondary endpoints will include the occurrence of adverse events such as pneumonia, stroke or myocardial infarction and evaluation of the external validity of the study. This large, multicentre, register-based randomised controlled trial could potentially shift the treatment of uFNFs in older patients towards primary hip arthroplasty in order to improve the outcome. The trial is registered at www.clinicaltrials.gov (NCT03966716); May 29, 2019.

Dementia is a serious and growing health problem, and since most people with dementia live at home, caring responsibilities generally fall on family members. Caregivers are often inadequately supported by formal health services and have poorer psychological and physical health. Our study aimed to compare the contributions of publications from different countries, institutions and authors and present a bibliometric analysis to determine the hotspots and trends in research concerning the health of and interventions for family dementia caregivers. Studies published during 1988–2018 were extracted from the Science Citation Index Expanded of the Web of Science. Each abstract of publications was evaluated to obtain the basic information. A bibliometric analysis was used to evaluate the number or cooperation networks of publications, countries, institutions, journals, citations, authors, references, and keywords. The resulting articles were analyzed descriptively, and the publication keywords were visualized using VOSviewer. Five hundred forty-two articles were identified. The annual number of relevant publications has steadily increased since approximately 2006. The USA has the highest number of publications (36.2%), followed by the UK (12.9%). China entered the field late, but research conducted in China has rapidly developed. The most productive institution, journal, and author in this field are University College London, the Journal of the American Geriatrics Society, and Orrell M from the UK, respectively. A co-occurrence analysis of the keywords reveals a mainstream research focus on burden, depression, quality of life, and corresponding interventions for people with dementia caregivers. The keywords “psychosocial intervention”, “long-term”, “e-learning/online”, “communication”, and “qualitative research” reflect the latest hotspots, appearing in approximately 2017–2018. Our study details the performance statistics, main topics and trends research on the health of and interventions for dementia caregivers from 1988 to 2018 and provides a comprehensive analysis.

With increasing age, having multiple chronic conditions is the norm. It is of importance to study how co-existence of diseases affects functioning and mortality among older persons. Complex multimorbidity may be defined as three or more conditions affecting at least three different organ systems. The aim of this study was to investigate how complex multimorbidity affects activities of daily living and mortality amongst older Norwegians. Participants were 60–69-year-olds at baseline in the Nord-Trøndelag Health Study 1995-1997 (HUNT2) n = 9058. Multinomial logistic regression models were used to investigate the association between complex multimorbidity in HUNT2, basic and instrumental activities of daily living in HUNT3 (2006–2008) and mortality during follow-up (n = 5819/5836). Risk ratios (RR) and risk differences (RD) in percentage points (pp) with 95% confidence intervals (CI) were reported. 47.8% of 60–69-year-olds met the criteria of complex multimorbidity at baseline (HUNT2). Having complex multimorbidity was strongly associated with the need for assistance in IADL in HUNT3 11 years later (RR = 1.80 (1.58–2.04) and RD = 8.7 (6.8–10.5) pp) and moderately associated with mortality during the follow-up time (RR = 1.22 (1.12–1.33) and RD = 5.1 (2.9–7.3) pp). Complex multimorbidity was to a lesser extent associated with basic activities of daily living 11 years later (RR = 1.24 (0.85–1.83) and RD = 0.4 (− 0.3–1.1) pp). This is the first study to show an association between complex multimorbidity and activities of daily living. Complex multimorbidity should receive more attention in order to prevent future disability amongst older persons.

Older adults have the highest drug utilization due to multimorbidity. Although the number of people over age 70 is expected to double within the next decades, population-based data on their medication patterns are scarce especially in combination with polypharmacy and potentially inappropriate medication (PIM). Our objective was to analyse the frequency of polypharmacy, pattern of prescription (PD) and over-the-counter (OTC) drug usage, and PIMs according to age and gender in a population-based cohort of very old adults in Germany. Cross-sectional baseline data of the Berlin Initiative Study, a prospective cohort study of community-dwelling adults aged ≥70 years with a standardized interview including demographics, lifestyle variables, co-morbidities, and medication assessment were analysed. Medication data were coded using the Anatomical Therapeutic Chemical (ATC) classification. Age- and sex-standardized descriptive analysis of polypharmacy (≥5 drugs, PD and OTC vs. PD only and regular and on demand drugs vs regular only), medication frequency and distribution, including PIMs, was performed by age (

Health professionals working with older persons are not sufficiently aware of the sensory and functional difficulties experienced by older patients. Innovative educational activities, such as the aging-simulation experience, can facilitate this awareness. This study describes the effects of an aging-simulation experience on health professionals’ representations towards age-related limitations. 306 health professionals, enrolled in university training in geriatrics/gerontology in the 2015–2016 and 2016–2017 academic years, experienced an aging-simulation session wearing a special suit according to a predefined scenario. Before and after the aging-simulation experience, participants completed free association tests, with the inductive words vision, hearing, movement, fine dexterity and balance. Semantic categories were created from participants’ free evocations using a correspondence table manually produced in Excel 2013 for Windows (Microsoft Corporation, Redmond, Washington). Moreover, participants’ opinions on difficulties experienced by older people in relation to age-related limitations were studied using Likert scale questions. In total, 3060 free evocations were collected, and ten semantic categories were created. These categories were composed of participants’ geriatric knowledge, about age-related limitations, and participants’ feelings, about the experience of these limitations. These two aspects were impacted by the aging-simulation experience. Moreover, changes observed resulted in a better consideration of difficulties associated with age-related limitations. The aging-simulation experience is an effective educational tool to raise awareness among health professionals of age-related difficulties. This sensory activity allows health professionals to put themselves in the shoes of older patients and to feel age-related difficulties.

BackgroundThe health of the caregivers is crucial to sustain informal care provision, while multimorbidity is an important health risk concept. However, studies on the association between informal caregiving and physical multimorbidity are currently lacking. Therefore, we investigated this association in adults from 48 low- and middle-income countries (LMICs). MethodsCross-sectional data from 242,952 adults (mean age 38.4 years) participating in the World Health Survey 2002-2004 were analyzed. Informal caregivers were considered those who provided help in the past year to a relative or friend (adult or child) who has a long-term physical or mental illness or disability, or is getting old and weak. Nine physical conditions were assessed. Multivariable logistic regression analyses were conducted to assess associations between informal caregiving and physical multimorbidity, while the between-country heterogeneity in this relationship was studied with country-wise analyses. ResultsThe overall prevalence of informal caregiving and physical multimorbidity (i.e, ≥2 physical conditions) was 19.2% and 13.2%, respectively. Overall, caregivers had 1.40 [95% confidence interval (CI)=1.29-1.52] times higher odds for physical multimorbidity. This association was particularly pronounced in younger caregivers [e.g., 18-44 years: odds ratio (OR)=1.54; 95%CI=1.37-1.72], while this association was not statistically significant among those aged ≥65 years (OR=1.19; 95%CI=0.98-1.44). Country-wise analyses corroborated these findings and there was a negligible level of between-country heterogeneity (I2=24.0%). ConclusionsIn LMICs, informal caregivers (especially young caregivers) were more likely to have physical multimorbidity. This should be taken into account in policies that address the health and wellbeing of informal caregivers.

BACKGROUNDPhysical activity is linked to many positive health outcomes, stimulating the development of exercise programs. However, many falls occur whilst walking and so promoting activity might paradoxically increase fall rates, causing injuries and worse quality of life. The relationship between activity exposure and fall rates remains unclear. We investigated the relationship between walking activity (exposure to risk) and fall rates before and after an exercise program (V-TIME). METHODS109 elderly fallers, 38 people with mild cognitive impairment (MCI) and 128 people with Parkinson’s disease (PD) were randomly assigned to one of two active interventions: treadmill training only or treadmill training combined with a virtual reality component. Participants were tested before and after the interventions. Free-living walking activity was characterised by volume, pattern, and variability of ambulatory bouts using an accelerometer positioned on the lower back for one week. To evaluate that relationship between fall risk and activity, a normalized index was determined expressing fall rates relative to activity exposure (FRA index), with higher scores indicating a higher risk of falls per steps taken. RESULTSAt baseline the FRA index was higher for people with PD compared to those with MCI and elderly fallers. Walking activity did not change after the intervention for the groups but the FRA index decreased significantly for all groups (p≤0.035). CONCLUSIONSThis work showed that V-TIME interventions reduced falls risk without concurrent change in walking activity. We recommend using the FRA index in future fall prevention studies to better understand the nature of intervention programs.

BackgroundHow cerebrovascular disease and neurodegeneration affect each other to impact cognition is not yet known. We aimed to test whether Alzheimer’s disease-signature (AD) cortical thickness mediates the association between cholinergic white matter lesion load and change in domain-specific cognition. MethodsClinically stroke-free participants from the Northern Manhattan Study with both regional white matter hyperintensity volume (WMHV) and gray matter measurements were included (N = 894). Tract-specific WMHVs were quantified through FSL using the Johns Hopkins University white matter tract atlas. We used Freesurfer 5.1 to estimate regional cortical thickness. We fit structural equation models, including multiple indicator latent change score models, to examine associations between white matter hyperintensity volume (WMHV) in cholinergic tracts, AD-signature region cortical thickness (CT), and domain-specific cognition. ResultsOur sample (N = 894) had a mean (SD) age = 70 (9) years, years of education = 10 (5), 63% women, and 67% Hispanics/Latinos. Greater cholinergic WMHV was significantly related to worse processing speed at baseline (standardized β = −0.17, SE = 0.05, p = .001) and over time (standardized β = −0.28, SE = 0.09, p = .003), with a significant indirect effect of AD-signature region CT (baseline: standardized β = −0.02, SE = 0.01, p = .023; change: standardized β = −0.03, SE = 0.02, p = .040). ConclusionsCholinergic tract WMHV is associated with worse processing speed, both directly and indirectly through its effect on AD-signature region CT.

This study was designed to determine whether and how the sympathetic nervous system (SNS) regulates motoneuron axon function and neuromuscular transmission in young (3-4 month) and geriatric (31-month) mice. Our approach included sciatic-peroneal nerve immunolabeling co-registration, and electrophysiological recordings in a novel mouse ex-vivo preparation, thesympathetic-peroneal nerve-lumbricalis muscle (SPNL). Here, the interaction between the motoneuron and SNS at the neuromuscular junction (NMJ) and muscle innervation reflect the complexity of the living mouse. Our data show that electrical stimulation of the sympathetic neuron at the paravertebral ganglia chain enhances motoneuron synaptic vesicle release at the NMJ in young mice, while in geriatric mice, this effect is blunted. We also found that blocking β-AR prevents the sympathetic neuron from increasing NMJ transmission. Immunofluorescence co-expression analysis of immunolabeled ARs with choline acetyltransferase-, tyrosine hydroxylase-, or calcitonin gene-related peptide immunoreactive axons showed that α2B-AR is found mainly in sympathetic neurons, β1-AR in sympathetic- and motor-neurons, and both decline significantly with aging. In summary, this study unveils the molecular substrate accounting for the influence of endogenous sympathetic neurons on motoneuron-muscle transmission in young mice and its decline with aging.

BackgroundThe contribution of cerebral small vessel disease (cSVD) to the pathogenesis of frailty remains uncertain. We aimed to examine the associations between cSVD with progression of frailty in a population-based study of older people. MethodsPeople aged between 60 and 85 years were randomly selected form the electoral roll to participate in the Tasmanian Study on Cognition and Gait. Participants underwent self-reported questionnaires, objective gait, cognitive and sensorimotor testing over three phases ranging between 2005 and 2012. These data were used to calculate a 41 item frailty index at three time points. Baseline brain magnetic resonance imaging was performed on all participants to measure cSVD. Generalized mixed models were used to examine associations between baseline cSVD and progression of frailty, adjusted for confounders of age, sex, level of education and total intracranial volume. ResultsAt baseline (n=388) mean age was 72 years (SD 7.0), 44% were female and the median frailty index score was 0.20 (IQR 0.12, 0.27). In fully adjusted models higher burden of baseline WMH was associated with frailty progression over 4.4 years (β 0.03 95%CI 0.01,0.05; p=0.004) independent of other SVD markers. Neither baseline infarcts (p =0.23), nor microbleeds at baseline (p=0.65) were associated with progression of frailty. ConclusionWe provide evidence for an association between baseline white matter hyperintensities and progression of frailty. Our findings add to a growing body of literature suggesting WMH is a marker for frailty.

BackgroundFrailty is a common condition among older adults increasing risk of adverse outcomes including mortality; however, little is known about the incidence or risk of specific causes of death among frail individuals. MethodsData came from the Health and Retirement Study (2004 – 2012), linked to underlying cause-of-death information from the National Death Index (NDI). Community-dwelling HRS participants aged 65 and older who completed a general health interview and physical measurements (n=10,490) were included in analysis. Frailty was measured using phenotypic model criteria – exhaustion, low weight, low energy expenditure, slow gait, and weakness. Underlying causes of death were determined using International Classification of Diseases, Version 10 codes. We used Cox proportional hazards and competing risks regression models to calculate and compare incidence of cause-specific mortality by frailty status. ResultsDuring follow-up, pre-frail and frail older adults had significantly greater hazard of all-cause mortality compared to individuals without symptoms (adjusted hazard ratio (HR) pre-frail: 1.85, 95% CI: 1.51, 2.25; HR frail: 2.75, 95% CI: 2.14, 3.53). Frailty was associated with 2.96 (95% CI: 2.17, 4.03), 2.82 (95% CI: 2.02, 3.94), 3.48 (95% CI: 2.17, 5.59) and 2.87 (95% CI: 1.47, 5.59) times greater hazard of death from heart disease, cancer, respiratory illness, and dementia, respectively. ConclusionsSignificantly greater risk of mortality from several different causes should be considered alongside the potential costs of screening and intervention for frailty in subspecialty and general geriatric clinical practice. Findings may help investigators estimate the potential impact of frailty reduction approaches on mortality.

Negative early-life exposures have been linked to a host of poor adult health outcomes, but are such early exposures associated with cellular senescence decades later? This study uses data from the Health and Retirement Study to examine the association between six childhood exposure domains (e.g., socioeconomic disadvantage, risky parental behavior) and a biomarker of aging, telomere length, among 4,935 respondents. Telomere length is obtained from DNA of cells found in saliva and is measured as the telomere repeat copy number to single gene copy number ratio (T/S). Men who as children were exposed to risky parental behaviors or who reported risky adolescent behaviors have shorter telomeres (respectively: b=-0.031, p=0.052; b=-0.041, p=0.045); however, these relationships are attenuated after adjusting for adult risks and resources. Among women, parental substance abuse is associated with shorter telomeres even after adjusting for adult risks and resources (b=-0.041, p=0.005). In addition, men and women whose mother lived at least until the age of 85 have longer telomeres than those without a long-lived mother (respectively: b=0.021, p=0.045; b=0.032, p=0.005). Taken together, the ways in which early-life exposures are associated with adult telomeres vary for men and women.

Objectives The association between serum levels of vitamin D and frailty in older Korean adults was examined. Study design Cross-sectional study. Older people living in the community across 10 study centers throughout South Korea. The baseline data (2016-2017) of 2872 participants aged 70-84 years in the Korean Frailty and Aging Cohort Study were evaluated. Main outcome measures Serum vitamin D level was assessed with an electro-chemiluminescence immunoassay. Frailty was defined using Fried’s frailty index. A multinomial logistic regression analysis was used to examine the association between serum levels of vitamin D and frailty. Results The percentages of those with serum vitamin D levels of <25 nmol/L, 25-49 nmol/L, 50-74 nmol/L, and ≥75 nmol/L were 4.1%, 37.0%, 37.8%, and 21.0%, respectively. The prevalence of frailty was 9.7%. Those with lower serum vitamin D levels, compared with ≥75 nmol/L, tended to have higher odds of being frail than being non-frail (OR: 1.58, 95% CI: 1.05-2.39 for 50-74 nmol/L; OR: 1.49, 95% CI: 0.98-2.26 for 25-49 nmol/L; OR: 1.37, 95% CI: 0.65-2.88 for <25 nmol/L). Among the components of frailty, low grip strength was significantly associated with lower serum levels of vitamin D. Conclusions Low serum levels of vitamin D are associated with an increased likelihood of frailty in community-dwelling older adults, suggesting a potentially protective role of vitamin D against frailty.

Older adults are at increased risk of malnutrition, which is associated with poorer health, quality of life, and worse disease outcomes. This study identifies predictors of incident malnutrition using data from a subsample (n = 1,841) of The Irish Longitudinal Study on Ageing. Participants were excluded if they were less than 65 years, missing body mass index data at baseline or follow-up, missing baseline weight loss data or malnourished at baseline (body mass index <20 kg/m2 or unplanned weight loss ≥4.5 kg in the previous year). Logistic regression analysis was performed with incident malnutrition (body mass index <20 kg/m2 and/or calculated weight loss >10% over follow-up) as the dependent variable. Factors showing significant (p < .05) univariate associations with incident malnutrition were entered into a multivariate model. The analysis was then repeated, stratified by sex. The 2-year incidence of malnutrition was 10.7%. Unmarried/separated/divorced status (vs married but not widowed), hospitalization in the previous year, difficulties walking 100 m, or climbing stairs independently predicted incident malnutrition at follow-up. When examined by sex, hospitalization in the previous year, falls during follow-up, and self-reported difficulties climbing stairs predicted malnutrition in males. Receiving social support and cognitive impairment predicted malnutrition in females. The development of malnutrition has a range of predictors. These can be assessed using simple questions to identify vulnerable persons.

We evaluated effects of calorie restriction (CR: consuming 60–65% of ad libitum [AL] intake) initiated late-in-life with or without acute exercise on insulin-stimulated glucose uptake (ISGU) of skeletal muscle by studying four groups of 26-month-old rats: sedentary-AL, sedentary-CR (8-week duration), 3 hours post-exercise (3hPEX)-AL and 3hPEX-CR. ISGU was determined in isolated epitrochlearis muscles incubated ± insulin. Muscles were assessed for signaling proteins (immunoblotting) and lipids (mass spectrometry). ISGU from sedentary-CR and 3hPEX-AL exceeded sedentary-AL; 3hPEX-CR exceeded all other groups. Akt (Ser473, Thr308) and Akt substrate of 160 kDa (AS160; Ser588, Thr642, Ser704) phosphorylation levels tracked with ISGU. Among the 477 lipids detected, 114 were altered by CR (including reductions in 15 of 25 acylcarnitines), and 27 were altered by exercise (including reductions in 18 of 22 lysophosphatidylcholines) with only six lipids overlapping between CR and exercise. ISGU significantly correlated with 23 lipids, including: acylcarnitine 20:1 (r = .683), lysophosphatidylethanolamine19:0 (r = −.662), acylcarnitine 24:0 (r = .611), and plasmenyl-phosphatidylethanolamine 37:5 (r = −.603). Muscle levels of ceramides (a lipid class previously linked to insulin resistance) were not altered by CR and/or exercise nor significantly correlated with ISGU, implicating other mechanisms (which potentially involve other lipids identified in this study) for greater ISGU and Akt and AS160 phosphorylation with these interventions.

Physical activity has positive effects on brain health and cognitive function throughout the life span. Thus far, few studies have examined the effects of physical activity on white matter microstructure and psychomotor speed within the same, population-based sample (critical if conclusions are to extend to the wider population). Here, using diffusion tensor imaging and a simple reaction time task within a relatively large population-derived sample (N = 399; 18–87 years) from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN), we demonstrate that physical activity mediates the effect of age on white matter integrity, measured with fractional anisotropy. Higher self-reported daily physical activity was associated with greater preservation of white matter in several frontal tracts, including the genu of corpus callosum, uncinate fasciculus, external capsule, and anterior limb of the internal capsule. We also show that the age-related slowing is mediated by white matter integrity in the genu. Our findings contribute to a growing body of work, suggesting that a physically active lifestyle may protect against age-related structural disconnection and slowing.

Telomeres progressively shorten with age, and it has been proposed that critically short and dysfunctional telomeres contribute to aging and aging-associated diseases in humans. For many years it was thought that telomere erosion was strictly a consequence of the “end replication problem,” or the inability of replicative polymerases to completely duplicate linear DNA ends. It is becoming increasingly evident, however, that telomere shortening of cultured human cells is also caused because of other replication defects in telomeric repeats, those that cause fragile telomeres and other aberrant telomeric structures that can be detected on metaphase chromosomes. Whether these replication defects contribute to telomere erosion also in human tissues is currently unknown. By analyzing peripheral blood mononuclear cells from a total of 35 healthy subjects ranging in age from 23 to 101 years, we demonstrated that telomeres increasingly display aberrant structures with advancing donor age. Although the percentages of fragile telomeres increased only until adulthood, the percentages of chromosomes displaying sister telomere loss and sister telomere chromatid fusions increased consistently throughout the entire human life span. Our data, therefore, suggest that telomeric replication defects other than the end replication problem contribute to aging-associated telomere erosion in humans.

Experimental evidence to date largely supports an association between the stress hormone cortisol and cognitive performance. Older adults, in particular, may be vulnerable to the neurotoxic effects of prolonged increases in cortisol; however, the assessment of chronic hormone levels has previously been challenging. Hair cortisol analysis has advantages over other cortisol metrics for this purpose as it facilitates the assessment of total hormone secretion over several months. Cortisol and cortisone were measured in the scalp hair of 1,876 older adults from The Irish Longitudinal Study on Ageing. Participants underwent a battery of cognitive tests assessing global function, memory, executive function, and processing speed. After adjustment for hair characteristics, demographics, metabolic risk factors, cardiovascular conditions, and depression, regression analysis revealed an inverse relationship of hair glucocorticoids to immediate (cortisol: β = –.12, p = .032; cortisone: β = –.021, p = .036) and delayed (cortisol: β = –.13, p = .003; cortisone: β = –.23, p = .006) word recall performance. They were also associated with more errors on the Mini-Mental State Examination (cortisol: incidence rate ratio (IRR) = 1.06, p = .008; cortisone: IRR = 1.14, p = .002) and Montreal Cognitive Assessment (cortisone: IRR = 1.06, p = .015). Higher hair glucocorticoids are inversely associated with memory and global cognition in a population-based sample of older adults. Future work should explore the prognostic significance of these findings.

BackgroundThis study examines the relationship between self-reported instances of major discrimination and inflammation among older adults, and explores whether this relationship varies in accordance with race/ethnicity. We hypothesized that self-reported instances of major discrimination would be associated with higher levels of high-risk inflammation and that this relationship would be stronger for racial/ethnic minorities than whites. MethodsData from the 2006/2008 Health and Retirement Study, an ongoing biennial nationally representative sample of older adults in the United States, were used to collect measures of self-reported instances of major discrimination and high-risk C-reactive protein (CRP), which was assayed from blood samples. Modified Poisson regression with robust standard errors was applied to estimate the prevalence ratios of self-reported instances of major discrimination, as it relates to high-risk CRP (CRP ≥ 22 kg/m2), and test whether this relationship varies by race/ethnicity. ResultsRespondents who experienced any instances of major discrimination had a higher likelihood of high-risk CRP (prevalence ratio [PR]: 1.14, 95% confidence interval [CI] = 1.07–1.22) than those who did not report experiencing any instances of major discrimination. This association was independent of differences in newly diagnosed health conditions and socioeconomic status. The relationship between any self-reported instance of major discrimination and high-risk CRP was weaker for blacks than whites (PR: 0.81, 95% CI = 0.69–0.95). ConclusionsOur study confirms that self-reported instances of major lifetime discrimination is a psychosocial factor that is adversely associated with high-risk CRP among older adults; this association is especially pronounced among older whites. Future studies among this population are required to examine whether the relationship between self-reported instances of major discrimination and high-risk CRP changes over time.

I read an interesting article by Tabara et al., which examined the association of advanced glycation end products (AGEs), evaluated by skin autofluorescence (SAF), with musculoskeletal factors in a large general population (1). In this cross-sectional study, SAF was measured on the middle finger of nondominant hand using the AGE sensor RQ-AG01J (SHARP Life Science Co., Kobe, Japan). The authors found in their Japanese cohort of 9,203 individuals that SAF was inversely associated with skeletal muscle mass index, bone mineral density evaluated by speed of sound in the calcaneal bone, and hip flexion and abduction strengths, all of which were independent of covariates, including age, sex, body mass index, C-reactive protein, and estimated glomerular filtration rate (1). AGEs have been shown to alter the structural integrity of extracellular matrix proteins in skeletal muscles and bones, whereas AGEs and their receptor RAGE interaction not only inhibit osteoblast differentiation and proliferation, but also induce muscle atrophy and dysfunction in cell culture and animal models (1–3). Moreover, SAF in the dominant forearm measured by the AGE Reader (AGE Reader-SAF) (DiagnOptics Technologies BV, Groningen, the Netherlands) has also been shown to correlate with low skeletal muscle mass as well as low skeletal muscle and bone strengths in a general population (1,2). Based on these findings, the authors conclude that accumulation of AGEs in skeletal muscles and bones might exert harmful effects on musculoskeletal systems and SAF-AGE levels measured by the AGE sensor (AGE sensor-SAF) is highly likely to be a risk marker of musculoskeletal frailty. However, I think that the following critical issues should be clarified to draw such a conclusion.

BackgroundEvidence suggests the pivotal contribution of nutrition as a modifiable risk factor for sarcopenia. The present cross-sectional study characterized the nutritional and metabolic profile of sarcopenia through an extensive exploration of a wide array of blood biomarkers related to muscle protein metabolism and transcriptomic signatures in community-dwelling elderly adults. MethodsAmong 189 older individuals with a mean age of 73.2 years, sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia criteria based on appendicular lean mass measured by dual-energy X-ray absorptiometry scan, muscle strength, and gait speed. Nutritional status was evaluated using the mini-nutritional assessment (MNA). In addition, we assessed specific blood biomarkers of nutritional status (plasma essential amino acids [EAAs], vitamins), nicotine-derived metabolites, and an extensive microarray analysis from peripheral blood mononuclear cells. ResultsMalnutrition defined by low MNA score was independently associated with sarcopenia (p < .001). Sarcopenic elderly showed lower body mass index and leptin and higher adiponectin and high-density lipoproteins. Levels of EAAs including lysine, methionine, phenylalanine, threonine, as well as branched-chain AAs and choline, were inversely associated with sarcopenia. Furthermore, nicotine metabolites (cotinine and trans-3′-hydroxycotine) and vitamin B6 status were linked to one or more clinical and functional measures of sarcopenia. Differentially expressed genes and ingenuity pathway analysis supported the association of nutrition with sarcopenia. ConclusionsHerein, the characterization of a nutritional and metabolic signature of sarcopenia provides a firm basis and potential identification of specific targets and directions for the nutritional approach to the prevention and treatment of sarcopenia in aging populations.

The liver endothelium plays a key role in the progression and resolution of liver diseases in young and adult individuals. However, its role in older people remains unknown. We have herein evaluated the importance of the sinusoidal endothelium in the pathophysiology of acute liver injury, and investigated the applicability of simvastatin, in aged animals. Eighteen-months-old male Wistar rats underwent 60 minutes of partial warm ischemia followed by 2 hours of reperfusion (WIR). A group of aged rats received simvastatin for 3 days before WIR. Endothelial phenotype, parenchymal injury, oxidative and nitrosative stress, and fenestrae dynamics were analyzed. The effects of WIR and simvastatin were investigated in primary LSEC from aged animals. The results of this study demonstrated that WIR significantly damages the liver endothelium and its effects are markedly worse in old animals. WIR-aged livers exhibited reduced vasodilation and sinusoidal capillarization, associated with liver damage and cellular stress. Simvastatin prevented the detrimental effects of WIR in aged livers. In conclusion, the liver sinusoidal endothelium of old animals is highly vulnerable to acute insult, thus targeted protection is especially relevant in preventing liver damage. Simvastatin represents a useful therapeutic strategy in aging.

BackgroundCross-sectional studies indicate an age-related decline in vitamin B6 status. Because longitudinal studies are lacking, the present study investigates the long-term association between age and vitamin B6 status in older adults by considering potential confounding factors. MethodsThe study population consists of 249 women and 111 men aged ≥ 60 years, who had at least three follow-ups between 1996 and 2014 with complete data records on relevant parameters. Vitamin B6 status was assessed by serum pyridoxal 5′-phosphate (PLP) concentrations measured by high-performance liquid chromatography. Linear mixed models were used to analyze the influence of age, sex, body composition, supplements, diet, lifestyle, and serum creatinine on PLP concentrations. ResultsAt baseline, 37% of the subjects showed PLP concentrations < 30 nmol/L and more than half failed to meet the recommended dietary intake. Longitudinal analyses revealed that age, use of supplements and protein intake were positive determinants of PLP concentrations, whereas body fat showed a negative impact. No influence of sex, dietary vitamin B6 intake, lifestyle factors or serum creatinine on PLP concentrations was found. ConclusionThe present study provides no evidence that in the course of aging PLP concentrations decline between 60 and 90 years. However, age-related changes in body composition, such as an increased ratio of fat mass to fat-free mass may negatively affect vitamin B6 status.

BackgroundAnticholinergic and sedative medications are frequently prescribed to older individuals. These medications are associated with short-term cognitive and physical impairment, but less is known about long-term associations. We therefore examined whether over 20 years cumulative exposure to these medications was related to poorer cognitive and physical functioning. MethodsOlder adult participants of the Longitudinal Aging Study Amsterdam (LASA) were followed from 1992 to 2012. On seven measurement occasions, cumulative exposure to anticholinergic and sedative medications was quantified with the drug burden index (DBI), a linear additive pharmacological dose–response model. Cognitive functioning was assessed with the Mini-Mental State Examination (MMSE), Alphabet Coding Task (ACT, three trials), Auditory Verbal Learning Test (AVLT, learning and retention condition), and Raven Colored Progressive Matrices (RCPM, two trials). Physical functioning was assessed with the Walking Test (WT), Cardigan Test (CT), Chair Stands Test (CST), Balance Test (BT), and self-reported Functional Independence (FI). Data were analyzed with linear mixed models adjusted for age, education, sex, living with a partner, BMI, depressive symptoms, comorbidities (cardiovascular disease, diabetes, cancer, COPD, osteoarthritis, CNS diseases), and prescribed medications. ResultsLongitudinal associations were found of the DBI with poorer cognitive functioning (less items correct on the three ACT trials, AVLT learning condition, and the two RCPM trials) and with poorer physical functioning (longer completion time on the CT, CST, and lower self-reported FI). ConclusionsThis longitudinal analysis of data collected over 20 years, showed that higher long-term cumulative exposure to anticholinergic and sedative medications was associated with poorer cognitive and physical functioning.

The rate of gastric emptying is a major determinant of the hypotensive response to a meal. Cross-sectional studies suggest that healthy aging is associated with a modest slowing of gastric emptying. We aimed to determine longitudinal changes in the blood pressure (BP) response to, and gastric emptying of, glucose in healthy older people. Thirty-three participants (77.0 ± 0.7 years) had baseline and follow-up measurements after 5.8 ± 0.1 years. Participants consumed a 300-mL drink containing 75 g glucose and 150 mg C13-acetate. BP and heart rate (HR) were measured at 5-minute intervals for 120 minutes after the drink. Exhaled breath was collected to calculate the gastric 50% emptying time. The prevalence of postprandial hypotension (PPH) doubled from 9.1% to 18.2%. Gastric emptying was slower at follow-up (p = .04). The fall in systolic BP (SBP) was related directly to the rate of gastric emptying at both the initial study (r = .54, p = .005) and at follow-up (r = .41, p = .04). The change in the maximum fall in SBP was related to the increase in baseline SBP (r = −.63, p < .001). In conclusion, in healthy older people over a period of ~5.8 years, there was an increased prevalence of PPH and a modest slowing of gastric emptying. The latter was related directly to a greater hypotensive response.

BackgroundAir pollution has been associated with various health outcomes. Its effect on hand-grip strength, a measurement of the construct of muscle strength and health status, remains largely unknown. MethodsWe used the survey data from 31,209 adults ≥ 50 years of age within Wave 1 of the Study on Global AGEing and Adult Health in six low- and middle-income countries. The outdoor concentration of fine particulate matter pollution (PM2.5) was estimated using satellite data. Domestic fuel type and ventilation were used as indicators of indoor air pollution. We used multilevel linear regression models to examine the association between indoor and outdoor air pollution and hand-grip strength, as well as the potential effect modifiers. ResultsWe found inverse associations between both indoor and outdoor air pollution and hand-grip strength. Each 10 μg/m3 increase in 3 years’ averaged concentrations of outdoor PM2.5 corresponded to 0.70 kg (95% CI: −1.26, −0.14) lower hand-grip strength; and compared with electricity/liquid/gas fuel users, those using solid fuels had lower hand-grip strength (β = −1.25, 95% CI: −1.74, −0.75). However, we did not observe a statistically significant association between ventilation and hand-grip strength. We further observed that urban residents and those having a higher education level had a higher association between ambient PM2.5 and hand-grip strength, and men, young participants, smokers, rural participants, and those with lower household income had higher associations between indoor air pollution and hand-grip strength. ConclusionThis study suggests that both indoor and outdoor air pollution might be important risk factors of poorer health and functional status as indicated by hand-grip strength.

Multimorbidity is widely recognized as having adverse effects on health and wellbeing and may threaten the ability of older adults to live independently. Much of what is known about multimorbidity rests on research that has largely focused on one point in time, or from a static perspective. Given that there remains a lack of agreement in the field on how to standardize multimorbidity definitions and measurement, it is not surprising that analyzing and predicting multimorbidity development, progression over time, and its impact are still largely unaddressed. As a result, there are important gaps and challenges to measuring and studying multimorbidity in a longitudinal context. This Research Practice perspective summarizes pressing challenges and offers practical steps to move the field forward.

BackgroundAging is characterized by chronic inflammation plus loss of muscle mass and strength, termed sarcopenia. Human leukocyte antigen (HLA) types are drivers of autoimmune disease, although with limited penetrance. We tested whether autoimmune diagnoses are associated with sarcopenia, and whether HLA types and related genetic variants are associated with sarcopenia in autoimmune disease-free older people. MethodsData were collected from 181,301 UK Biobank European descent volunteers aged 60–70 with measured hand grip strength and impedance. Logistic regression analysis estimated HLA type and sarcopenia associations, adjusted for confounders and multiple testing. ResultsHaving any autoimmune diagnosis was associated with sarcopenia (odds ratio [OR] 1.83, 95% confidence interval (CI) 1.74–1.92, p = 4.0*10−125). After excluding autoimmune diagnoses, 6 of 100 HLA types (allele frequency >1%) were associated with sarcopenia (low grip strength and muscle mass). Having two HLA-DQA1*03:01 alleles increased odds of sarcopenia by 19.3% (OR 1.19, CI 1.09–1.29, p = 2.84*10–5), compared to no alleles. Having ≥6 of the 12 HLA alleles increased sarcopenia odds by 23% (OR 1.23, CI 1.12–1.35, p = 7.28*10–6). Of 658 HLA region non-coding genetic variants previously implicated in disease, 4 were associated with sarcopenia, including rs41268896 and rs29268645 (OR 1.08, CI 1.05–1.11, p = 1.06*10–8 and 1.07, CI 1.04–1.09, p = 1.5*10–6, respectively). Some HLA associations with sarcopenia were greater in female participants. ConclusionAutoimmune diagnoses are strongly associated with sarcopenia in 60- to 70-year olds. Variation in specific HLA types and non-coding single nucleotide polymorphisms is also associated with sarcopenia in older carriers free of diagnosed autoimmune diseases. Patients with sarcopenia might benefit from targeted treatment of autoimmune processes.

BackgroundTo evaluate the discordance in frailty classification between the frailty index (FI) and the physical frailty phenotype (PFP) and identify factors discriminating those with discordant frailty classification from each other and from those for whom the assessments agree. MethodsA prospective observational study of older adults aged 65 and older selected from Medicare eligibility lists in four U.S. communities (n = 5,362). The PFP was measured by the Cardiovascular Health Study PFP. Participants meeting three or more of the five criteria were deemed frail. The FI was calculated as the proportion of deficits in an a priori selected set of 48 measures, and participants were classified as frail if FI is greater than 0.35. ResultsThe prevalence of frailty was 7.0% by the PFP and 8.3% by the FI. Of the 730 deemed frail by either instrument, only 12% were in agreement, whereas 39% were classified as frail by the PFP, but not the FI, and 48% were classified as frail by the FI, but not the PFP. Participants aged 65–72 years or with greater disease burden were most likely to be characterized as being FI-frail, but not PFP-frail. The associations of frailty with age and mortality were stronger when frailty was measured by the PFP rather than the FI. ConclusionsDespite comparable frailty prevalence between the PFP and the FI, there was substantial discordance in individual-level classification, with highest agreement existing only in the most vulnerable subset. These findings suggest that there are clinically important contexts in which the PFP and the FI cannot be used interchangeably.

BackgroundConsidering that mortality rate and deficit accumulation varies considerably in men and women, we performed a sex-stratified analysis of the association between an estimated frailty index (eFI) with 6-year mortality in the Activity and Function in the Elderly (ActiFE) Study. MethodsWe constructed an eFI using a score (0 [no deficit] to 1 [deficit]) from 32 baseline items representing multiple domains. eFI represents the sum of all scores divided by 32. Cox proportional hazards models adjusted for age, smoking, alcohol intake, and education were used to evaluate this association. ResultsAmong 1,204 participants (57.5% men), 18.5% men and 26.0% women were frail (eFI ≥ 0.2) with an age-adjusted mean eFI of 0.13 (95% confidence interval [CI] 0.12, 0.13) and 0.15 (95% CI 0.15, 0.16), respectively. Mortality rate in men (146 deaths) was 34.4 (95% CI 29.3, 40.5) and in women (50 deaths) 15.1 (95% CI 11.5, 19.9) per 1,000 person-years. A 0.1 increment of eFI was associated with a hazard ratio (HR) of 1.94 (95% CI 1.60, 2.35) in men and 2.06 (95% CI 1.58, 2.69) in women. Frail versus nonfrail men and women had a HR of 2.46 (95% CI 1.74, 3.48), and 2.98 (95% CI 1.55, 5.70), respectively. We detected sex differences in the order of the eight common contributor items to the eFI. ConclusionsWe observed a statistically significant difference for the age-adjusted eFI and the frailty prevalence in men and women. However, our analysis does not suggest the presence of effect modification by sex in the association with mortality.

BackgroundWe investigated whether carotid intima–media thickness is associated with measures of cerebral blood flow (CBF), white matter hyperintensities, and brain volume in a biracial cohort of middle-aged individuals. MethodsWe performed a cross-sectional cohort study based on data from a multicenter, population-based study Coronary Artery Risk Development in Young Adults. Using linear and logistic regression, we estimated the association of the composite intima–media thickness measured in three segments of carotid arteries (common carotid artery, carotid artery bulb, and internal carotid artery) with volume (cm3) and CBF (mL/100 g/min) in the total brain and gray matter as well as volume of white matter hyperintensities (cm3). ResultsIn the analysis, 461 participants (54% women, 34% African Americans) were included. Greater intima–media thickness was associated with lower CBF in gray matter (β=−1.36; p = .04) and total brain (β=−1.26; p = .04), adjusting for age, sex, race, education, and total brain volume. The associations became statistically nonsignificant after further controlling for cardiovascular risk factors. Intima–media thickness was not associated with volumes of total brain, gray matter, and white matter hyperintensities. ConclusionsThis study suggests that lower CBF in middle age is associated with markers of atherosclerosis in the carotid arteries. This association may reflect early long-term exposure to traditional cardiovascular risk factors. Early intervention on atherosclerotic risk factors may modulate the trajectory of CBF as people age and develop brain pathology.

BackgroundLittle is known about the patterns of end-of-life health care for older Mexican Americans with or without a diagnosis of Alzheimer’s disease and related dementias (ADRD). Our objective was to investigate the frequency of acute hospital admissions, intensive care unit use, and ventilator use during the last 30 days of life for deceased older Mexican American Medicare beneficiaries with and without an ADRD diagnosis. MethodsWe used Medicare claims data linked with survey information from 1,090 participants (mean age of death 85.1 years) of the Hispanic Established Populations for the Epidemiologic Studies of the Elderly. Multivariable logistic regression models were used to estimate the odds for hospitalization, intensive care unit use, and ventilator use in the last 30 days of life for decedents with ADRD than those without ADRD. Generalized linear models were used to estimate the risk ratio (RR) for length of stay in hospital. ResultsWithin the last 30 days of life, 64.5% decedents had an acute hospitalization (59.1% ADRD, 68.3% no ADRD), 33.9% had an intensive care unit stay (31.3% ADRD, 35.8% no ADRD), and 17.2% used a ventilator (14.9% ADRD, 18.8% no ADRD). ADRD was associated with significantly lower hospitalizations (odds ratio [OR] = 0.67, 95% confidence interval [CI] = 0.50–0.89) and shorter length of stay in hospital (RR = 0.77, 95% CI = 0.65–0.90). ConclusionHospitalization, intensive care unit stay, and ventilator use are common at the end of life for older Mexican Americans. The lower hospitalization and shorter length of stay in hospital of decedents with ADRD indicate a modest reduction in acute care use. Future research should investigate the impact of end-of-life planning on acute-care use and quality of life in terminally ill Mexican American older adults.

BackgroundStudies in some high-income countries have reported a potential decline in the prevalence of dementia. Improvements in cardiovascular health may be contributing to this decline. The objective was to examine trends in prevalence of dementia and survival with dementia for people accessing aged care in Australia. MethodsA retrospective study of older people who accessed long-term care 2008–2014 (n = 348,311) and home care 2005–2014 (n = 188,846) in Australia was developed. The age- and sex-standardized prevalence for dementia by year of access to aged care was determined using direct standardization. Generalized linear models were used to determine change in the prevalence of dementia over time and change in 1-year mortality for people who accessed long-term care. ResultsThe age- and sex-standardized prevalence (95% confidence interval) of dementia declined from 50.0% (49.6, 50.5) in 2008 to 46.6% (46.0, 47.2) in 2014 for people accessing long-term care (absolute change 2008–2014: −3.8 [−4.6, −3.1]) and for people accessing home care from 25.9% (25.0, 26.5) in 2005 to 20.9% (20.2, 21.7) in 2014 (absolute change 2005–2014: −5.2 [−6.2, −4.1]). This decline in dementia occurred in concurrence with a decline in cerebrovascular disease in long-term care but despite the prevalence of hypertension, diabetes, high cholesterol, malnutrition, obesity, depression, and head injury increasing. For people accessing long-term care, 1-year mortality remained stable over time. ConclusionsThe decline in prevalence of dementia for people accessing aged care services in Australia is critical to future projection estimates and for planning of services. Further research to determine contributing factors to the decline is needed.

BackgroundHuman life expectancy continues to rise in most populations. This rise not only leads to longer lives but also is accompanied by improved health at a given age, that is, recent cohorts show a reduction of biological age for a given chronological age. Despite or even because of the diversity of biomarkers of aging, an accurate quantification of a general shift in biological age across time has been challenging. MethodsHere, we compared age perception of facial images taken in 2001 over a decade and related these changes in age perception to changes in life expectancy. ResultsWe show that age perception changes substantially across time and parallels the progress in life expectancy. In 2012, people aged more than 70 years needed to look 2.3 years younger to be rated the same age as in 2002. ConclusionsOur results suggest that age perception reflects the past life events better than predicts future length of life, that is, it is written in your face how much you have aged so far. We draw this conclusion as age perception among elderly individuals paralleled changes in life expectancy at birth but not changes in remaining life expectancies. We suggest that changes in age perception should be explored for younger age classes to inform on aging processes, including whether aging is delayed or slowed with increasing life expectancy.

Animals undergoing calorie restriction (CR) often lower their body temperature to conserve energy. Brown adipose tissue (BAT) is stimulated through norepinephrine when rapid heat production is needed, as it is highly metabolically active due to the uncoupling of the electron transport chain from ATP synthesis. To better understand how BAT metabolism changes with CR, we used metabolomics to identify 883 metabolites that were significantly differentially expressed in the BAT of C57BL/6 mice, fed graded CR (10%, 20%, 30%, and 40% CR relative to their individual baseline intake), compared with mice fed ad libitum (AL) for 12 hours a day. Pathway analysis revealed that graded CR had an impact on the TCA cycle and fatty acid degradation. In addition, an increase in nucleic acids and catecholamine pathways was seen with graded CR in the BAT metabolome. We saw increases in antioxidants with CR, suggesting a beneficial effect of mitochondrial uncoupling. Importantly, the instigator of BAT activation, norepinephrine, was increased with CR, whereas its precursors l-tyrosine and dopamine were decreased, indicating a shift of metabolites through the activation pathway. Several of these key changes were correlated with food anticipatory activity and body temperature, indicating BAT activation may be driven by responses to hunger.

BackgroundThe objective of the study is to evaluate the prospective associations between antioxidant intake and incident frailty among older Australian men aged ≥75 years. MethodsSeven hundred and ninety-four men participated in a detailed diet history interview at the Concord Health and Ageing in Men Project (CHAMP) study third wave (considered baseline nutrition here) and 781 men participated at the fourth wave (considered 3-year follow-up here). The main outcome measurement was incident frailty at 3-year follow-up, using the Cardiovascular Health Study definition. Dietary adequacy of antioxidant intake was assessed by comparing participants’ median intakes of four dietary antioxidants (vitamin A, E, C, and zinc) to the nutrient reference values (NRVs). Attainment of the NRVs was incorporated into a dichotomized variable “poor” (meeting ≤2 antioxidants) or “good” (meeting ≥3 antioxidants) as the independent variable using the cut-point method. Also, intakes of each individual dietary antioxidant at baseline nutrition were categorized into quartiles. Analyses were performed using multinomial logistic regression. ResultsIncidence of pre-frailty was 53.0% and frailty was 6.4% at 3-year follow-up. Poor dietary antioxidant intake (meeting ≤2) at baseline nutrition was associated with incident frailty at 3-year follow-up in unadjusted (OR: 2.59 [95% CI: 1.47, 4.59, p = .001]) and adjusted (OR: 2.46 [95% CI: 1.10, 5.51, p = .03]) analyses. The lowest quartile of vitamin E intake (<7.08 mg/d) was significantly associated with incident frailty (OR: 2.46 [95% CI: 1.01, 6.00, p = .05]). ConclusionsPoor antioxidant intake, particularly vitamin E, is a plausible factor associated with incident frailty among older men. This supports the need for clinical trials of diets rich in antioxidants or possibly low-dose antioxidant supplements, for prevention of frailty.

The liver sinusoidal endothelial cells (LSECs) that make up the lining of the liver sinusoids play a vital, but frequently ignored, role in liver physiology, toxicology, and aging. For instance, the LSECs are responsible for a remarkably efficient scavenging of a great number of macromolecules and nanoparticles from the circulation (1). In addition, these cells are equipped with numerous open pores (30–250 nm), or fenestrae, allowing passive passage of macromolecules between the blood (ie, the sinusoidal lumen) and the hepatocytes. In this way, LSECs act like an efficient filter, contributing importantly to homeostasis. LSECs also pose a major challenge to the delivery of large molecule drugs and nano formulations, in that they efficiently scavenge these compounds, preventing them from reaching the tissues where their intended therapeutic effect is to take place. Moreover, certain drugs, of both small and large molecule size, have been shown to cause liver toxicity by having an initial adverse effect on LSECs (2).

Oh my! Times have changed and science has advanced dramatically since Louis Hellman published on aging and pregnancy outcomes in one of the very first articles in the Journals of Gerontology in 1946 (1). The times: Dr. Hellman stated that obstetricians arbitrarily determined that 35 years of age was the end of youth and beginning of old age for reproduction in women and particularly so for primiparous women, who were termed “elderly” at age 35. Pregnancy beyond this age was thought to be perilous for the mother and infant mostly due to toxemia, myomata (fibroids), and complications of middle-agedness (heart and kidney disease, diabetes). Currently, the age of 35 is not considered middle age, let alone old age, or elderly as the number of women waiting to have their families until later in life has risen steadily. Pregnancy outcome in women of advanced age has improved with advancements in perinatology, and it has been proposed that the definition of the period of obstetric risk be postponed until after age 40 or perhaps age 45 (2–4). In addition, diseases of the middle aged in 1946 differ markedly from those in the 21st century where gestational diabetes mellitus, hypertensive disorders, and pre-eclampsia are among the concerns of physicians today. In addition, life expectancy for women in 1940 was 65.2 years, whereas in 2017, this number is 81.1 years (5).

The results presented in Table 3 have been corrected to account for a miscalculation of the Charlson Comorbidity Index Score. The text on page 4 that describes the results for the increasing trend in the odds to have been hospitalized according the Charlson Comorbidity Index Score has also been corrected.

BackgroundCortisol is a key stress hormone implicated in the pathogenesis of many age-related diseases. Longitudinal information on cortisol exposure has been restricted to animal models and a small number of human studies. The purpose of the present study was to quantify longitudinal change in cortisol across the adult life span. MethodsWe conducted a prospective longitudinal study of 24-hour urinary free cortisol excretion from ages 20 to 90 years and older. Participants were 1,814 men and women from the Baltimore Longitudinal Study of Aging who provided a total of 5,527 urine specimens for analysis. The average duration of longitudinal follow-up was 6.6 years. The primary outcome measure was 24-hour urinary free cortisol to creatinine ratio (UFC/Cr) as determined by liquid chromatography/mass spectrometry. ResultsUFC/Cr follows a U-shaped pattern across the life span with decreases in UFC/Cr in the 20s and 30s, relative stability in the 40s and 50s, and increases thereafter. This pattern of change was robust with respect to adjustment for several potential confounding factors. ConclusionsAge-related changes in cortisol exposure raise important questions about the potential protective or exacerbating role of cortisol exposure in predicting medical, physiological, and behavioral outcomes.

Age-related changes in the liver sinusoidal endothelium, particularly the reduction in fenestrations, contribute to insulin resistance in old age. Metformin impacts on the aging process and improves insulin resistance. Therefore, the effects of metformin on the liver sinusoidal endothelium were studied. Metformin increased fenestrations in liver sinusoidal endothelial cells isolated from both young and old mice. Mice administered metformin in the diet for 12 months had increased fenestrations and this was associated with lower insulin levels. The effect of metformin on fenestrations was blocked by inhibitors of AMP-activated protein kinase (AMPK), endothelial nitric oxide synthase, and myosin light chain kinase phosphorylation. Metformin led to increased transgelin expression and structural changes in the actin cytoskeleton but had no effect on lactate production. Metformin also generated fenestration-like structures in SK-Hep1 cells, a liver endothelial cell line, and this was associated with increased ATP, cGMP, and mitochondrial activity. In conclusion, metformin ameliorates age-related changes in the liver sinusoidal endothelial cell via AMPK and endothelial nitric oxide pathways, which might promote insulin sensitivity in the liver, particularly in old age.

Idiopathic pulmonary fibrosis (IPF) is a progressive fatal lung disorder with an unknown etiology and very limited therapeutic options. The incidence and severity of IPF increase with advanced age, suggesting that aging is a major risk factor for IPF. The mechanism underlying the aging-related susceptibility to IPF, however, remains unclear. Cellular senescence, a permanent arrest of cell growth, has been increasingly recognized as an important contributor to aging and aging-related diseases, including IPF. Senescent cells have been identified in IPF lungs and in experimental lung fibrosis models. Removal of senescent cells pharmacologically or genetically improves lung function and reverses pulmonary fibrosis induced by different stimuli in experimental fibrosis models. Treatment with senolytic drugs also improves clinical symptoms in IPF patients. These intriguing findings suggest that cellular senescence contributes importantly to the pathogenesis of fibrotic lung diseases and targeting senescent cells may represent a novel approach for the treatment of fibrotic lung disorders. In this mini review, we summarize the recent advance in the field regarding the role of cellular senescence in fibrotic lung diseases, with a focus on IPF.