Embracing complexity of (brain) aging.

Aging is a multifactorial process occurring in a pathophysiological continuum which leads to organ and system functional loss. While aging is not a disease, its pathophysiological continuum predisposes to illness and multimorbidity clusters which share common biomolecular mechanisms-the pillars of aging. Brain aging and neurodegeneration share many hallmarks with other age-related diseases. The central nervous system is often the weakest link susceptible to the aging process and its deterioration, resulting in cognitive impairment and other symptoms; the aging process is associated with proteostasis collapse, stem cell exhaustion, repair mechanisms, altered brain nutrient sensing, endothelial changes, inflammation, oxidative distress, and energy unbalance, as well as other disturbances. These mechanisms are highly interwoven, and considerable research is aimed at their disentanglement and detection of their clinically relevant impact, particularly in order to identify pharmacological and non-pharmacological preventive and therapeutic strategies.

Which Comprehensive Geriatric Assessment (CGA) instruments are currently used in Germany: a survey.

BACKGROUND: The Comprehensive Geriatric Assessment (CGA) records geriatric syndromes in a standardized manner, allowing individualized treatment tailored to the patient's needs and resources. Its use has shown a beneficial effect on the functional outcome and survival of geriatric patients. A recently published German S1 guideline for level 2 CGA provides recommendations for the use of a broad variety of different assessment instruments for each geriatric syndrome. However, the actual use of assessment instruments in routine geriatric clinical practice and its consistency with the guideline and the current state of literature has not been investigated to date. METHODS: An online survey was developed by an expert group of geriatricians and sent to all licenced geriatricians (n = 569) within Germany. The survey included the following geriatric syndromes: motor function and self-help capability, cognition, depression, pain, dysphagia and nutrition, social status and comorbidity, pressure ulcers, language and speech, delirium, and frailty. Respondents were asked to report which geriatric assessment instruments are used to assess the respective syndromes. RESULTS: A total of 122 clinicians participated in the survey (response rate: 21%); after data cleaning, 76 data sets remained for analysis. All participants regularly used assessment instruments in the following categories: motor function, self-help capability, cognition, depression, and pain. The most frequently used instruments in these categories were the Timed Up and Go (TUG), the Barthel Index (BI), the Mini Mental State Examination (MMSE), the Geriatric Depression Scale (GDS), and the Visual Analogue Scale (VAS). Limited or heterogenous assessments are used in the following categories: delirium, frailty and social status. CONCLUSIONS: Our results show that the assessment of motor function, self-help capability, cognition, depression, pain, and dysphagia and nutrition is consistent with the recommendations of the S1 guideline for level 2 CGA. Instruments recommended for more frequent use include the Short Physical Performance Battery (SPPB), the Montreal Cognitive Assessment (MoCA), and the WHO-5 (depression). There is a particular need for standardized assessment of delirium, frailty and social status. The harmonization of assessment instruments throughout geriatric departments shall enable more effective treatment and prevention of age-related diseases and syndromes.

Focus on senescence: Clinical significance and practical applications.

The older population is increasing worldwide, and life expectancy is continuously rising, predominantly thanks to medical and technological progress. Healthspan refers to the number of years an individual can live in good health. From a gerontological viewpoint, the mission is to extend the life spent in good health, promoting well-being and minimizing the impact of aging-related diseases to slow the aging process. Biologically, aging is a malleable process characterized by an intra- and inter-individual heterogeneous and dynamic balance between accumulating damage and repair mechanisms. Cellular senescence is a key component of this process, with senescent cells accumulating in different tissues and organs, leading to aging and age-related disease susceptibility over time. Removing senescent cells from the body or slowing down the burden rate has been proposed as an efficient way to reduce age-dependent deterioration. In animal models, senotherapeutic molecules can extend life expectancy and lifespan by either senolytic or senomorphic activity. Much research shows that dietary and physical activity-driven lifestyle interventions protect against senescence. This narrative review aims to summarize the current knowledge on targeting senescent cells to reduce the risk of age-related disease in animal models and their translational potential for humans. We focused on studies that have examined the potential role of senotherapeutics in slowing the aging process and modifying age-related disease burdens. The review concludes with a general discussion of the mechanisms underlying this unique trajectory and its implications for future research.

Aging hallmarks, biomarkers, and clocks for personalized medicine: (re)positioning the limelight.

The rapidly increasing aging prevalence, complexity, and heterogeneity pose the scientific and medical communities in front of challenges. These are delivered by gaps between basic and translational research, as well as between clinical practice guidelines to improve survival and absence of evidence on personalized strategies to improve functions, wellbeing and quality of life. The triumphs of aging science sheding more and more light on mechanisms of aging as well as those of medical and technological progress to prolong life expectancy are clear. Currently, and in the next two to three decades, all efforts must be put in a closer interdisciplinary dialogue between biogerontologists and geriatricians to enable real-life measures of aging phenotypes to be used to uncover the physiological - and therefore translational - relevance of newly discovered aging clocks, biomarkers, and hallmarks.

Effectiveness of multi-professional educational interventions to train Comprehensive Geriatric Assessment (CGA) - a Systematic Review.

Introduction: As the world population ages, health and social care professionals are increasingly confronted with patients with chronic long-term conditions and multimorbidity, requiring an extensive assessment and integrated care management strategy. The aim of this paper was to systematically collect and assess evidence of interprofessional education and training strategies for Comprehensive Geriatric Assessment (CGA) to build a competent health workforce. Methods: A systematic review was conducted according to PRISMA guidelines and the databases Medline, CINAHL, Cochrane and Embase were searched for studies illustrating effectiveness of educational interventions for teaching and training CGA in an interprofessional context. Results: Based on 21 identified studies, a great variability and heterogeneity in duration, setting and design of the interventions was identified. Promising results were found in the domains analysed, ranging from knowledge and skills; practices and behaviour; patient health outcomes; attitudes and perceptions to collaboration and quality of care. Discussion: Education and training of transversal skills within a continuous learning approach is key to equip the health care workforce for successful CGA performance in an interprofessional environment. Conclusion: Further research in this field is recommended to strengthen the evidence-base towards development of a resilient and integrated health care workforce for an ageing population.

Effects of the Multicomponent Cognitive Training Program BrainProtect in Cognitively Healthy Adults: A Randomized Controlled Trial.

BACKGROUND: Cognitive integrity is a fundamental driver of health. The exact structure of strategies against cognitive impairment is still under debate. OBJECTIVE: To compare the short-term effects of a multicomponent cognitive training (BrainProtect) with those of general health counseling (GHC) on cognitive abilities and health-related quality of life (HRQoL) in healthy adults in Germany. METHODS: In this parallel randomized controlled trial (RCT), 132 eligible cognitively healthy adults (age ≥50 years, Beck Depression Inventory ≤9/63; Montreal Cognitive Assessment ≥26/30) were randomized to either GHC (N = 72) or to intervention with BrainProtect (intervention group, IG; N = 60). IG participants received 8 weekly sessions of 90 min of the group-based BrainProtect program focusing on executive functions, concentration, learning, perception, and imagination, plus nutritional and physical exercise units. Before and after intervention, all participants underwent neuropsychological testing and HRQoL evaluation, blinded for pretest. RESULTS: No significant training effect was observed for the primary endpoint of global cognition as assessed by CERAD-Plus-z Total Score (p = 0.113; ηp2 = 0.023). Improvements in several cognitive subtests were shown in the IG (N = 53) compared to the GHC (N = 62) without adverse events. Differences reached significance for verbal fluency (p = 0.021), visual memory (p = 0.013), visuo-constructive functions (p = 0.034), and HRQoL (p = 0.009). Significance was lost after adjustment, though several changes were clinically relevant. CONCLUSION: BrainProtect did not significantly impact global cognition in this RCT. Nevertheless, the results of some outcomes indicate clinically meaningful changes, so that a strengthening of the cognitive performance by BrainProtect cannot be excluded. Further studies with larger sample size are needed to confirm these findings.

On frailty and accelerated aging during SARS-Cov-2: senescence.

The COVID-19 pandemic is a burden for the worldwide healthcare systems. Whereas a clear age-dependent mortality can be observed, especially multimorbid and frail persons are at an increased risk. As bio-functional rather than calendrical age is in the meanwhile known to play a crucial role for COVID-19-related outcomes, aging-associated risk factors, overall prognosis and physiological age-related changes should be systematically considered for clinical decision-making. In this overview, we focus on cellular senescence as a major factor of biological aging, associated with organ dysfunction and increased inflammation (inflammaging).

The multidimensional prognostic index in hospitalized older adults: practicability with regard to time needs.

BACKGROUND: Comprehensive Geriatric Assessment (CGA) is decisive in patient-centered medicine of the aged individual, yet it is not systematically used. AIM: The aim of this study was to provide precise practice-relevant time expenditure data for the Multidimensional Prognostic Index (MPI), a questionnaire-based frailty assessment tool. METHODS: MPI was determined in ninety older multimorbid adults in three geriatric departments (cohorts 1, 2 and 3). The time needed to perform the MPI (tnpMPI) was recorded in minutes. Follow-up data were collected after 6 months. RESULTS: The median tnpMPI was 15.0 min (IQR 7.0) in the total collective. In the last visited cohort 3, the median was 10.0 min and differed significantly from cohorts 1 and 2 with medians of 15.5 and 15.0 (p < 0.001). CONCLUSION: These findings indicate, that MPI, as a highly informative frailty tool of individualized medicine, can be performed in an adequately practicable time frame.

A Tailored Discharge Program Improves Frailty and Mood in Patients Undergoing Usual Rehabilitative Care: A Randomized Controlled Trial.

OBJECTIVE: To investigate whether a tailored intersectoral discharge program (TIDP) impacts on multidimensional frailty, rehospitalization days, and patient-related outcome measures in older in-patients undergoing acute care and usual rehabilitative care. DESIGN: Randomized controlled trial of TIDP vs usual rehabilitative care with a 6-month follow-up, 2019-2020, and historical control with a 6-month follow-up, 2016-2019. SETTING AND PARTICIPANTS: Geriatric co-managed internal medicine ward of a metropolitan university hospital. One hundred-twelve multimorbid patients older than age 60 years were consecutively assessed for eligibility and inclusion (age ≥60 years, multimorbidity, admitted for treatment of acute disease, at least 2 geriatric syndromes requiring usual rehabilitative care, and able to consent) and signed informed consent, with 110 recruited and randomized to either TIDP or usual rehabilitative care. At discharge, 104 patients were alive in the intention-to-treat group, the 6-month follow-up was completed for 91 patients. A historical control group of 468 patients was included for comparison. INTERVENTION: TIDP as intervention included contact with treating general practitioner to discuss the further treatment plan, a structured medical and lifestyle counseling to patients and caregivers at admission as well as a discharge program with internist, geriatrician, and general practitioner in shared decision making with patients. METHODS: Fifty-four patients underwent TIDP, 53 patients underwent usual rehabilitative care only. Rehospitalization days at follow-up as primary endpoint; multidimensional frailty and prognosis (Multidimensional Prognostic Index, Geriatric Depression Scale, Rosenberg Self-Esteem Scale, quality of life, falls, mortality, home care service need, and need of long-term care at 1-, 3- and 6-month follow-up as secondary endpoints. RESULTS: TIDP (median age 76.0 years, 56% female) showed significantly improved Multidimensional Prognostic Index scores at discharge compared with usual rehabilitative care (median age 78.5 years, 58% female) (0.43 vs 0.49, P = .011). Compared with usual rehabilitative care, TIDP improved self-confidence (Rosenberg Self-Esteem Scale 13.9 vs 12.4, P = .009) and mood (Geriatric Depression Scale 4 vs 5, P = .027) at follow-up. Compared with historical control (median age 77.0 years, 39 % female), usual rehabilitative care patients showed significantly lower rehospitalization rates (53% vs 70%, P = .002) and lower mortality rates (13% vs 32%, P < .001). CONCLUSIONS AND IMPLICATIONS: A feasible TIDP improves frailty and mood in advanced age. In older patients undergoing potentially disabling acute treatments, usual rehabilitative care significantly reduces rehospitalization rates. Therefore, implementing geriatric treatment in general is useful to improve outcomes in older in-patients and a tailored discharge program can further increase the benefit for this frail population.

Biomarkers of aging in real life: three questions on aging and the comprehensive geriatric assessment.

Measuring intrinsic, biological age is a central question in medicine, which scientists have been trying to answer for decades. Age manifests itself differently in different individuals, and chronological age often does not reflect such heterogeneity of health and function. We discuss here the value of measuring age and aging using the comprehensive geriatric assessment (CGA), cornerstone of geriatric medicine, and operationalized assessment tools for prognosis. Specifically, we review the benefits of employing the multidimensional prognostic index (MPI), which collects information about eight domains relevant for the global assessment of the older person (functional and cognitive status, nutrition, mobility and risk of pressure sores, multi-morbidity, polypharmacy, and co-habitation), in the evaluation of the functional status, and in the prediction of health outcomes for older adults. Further integration of biological markers of aging into multidimensional prognostic tools is warranted, as well as actions which could facilitate prognostic assessments for older persons in all healthcare settings.

Influence of a 12-Month Structured Exercise Program on the Micronutrient-Cognitive Fitness-Physical Association Profiles in Mild Cognitive Impairment.

Background: Preventive lifestyle strategies have shown promise to slow down or prevent age-related cognitive decline. However, evidence on the reciprocal longitudinal relationships between nutrition biomarkers and cognitive and physical performance is lacking. Studying nutritional, cognitive, and physical profiles over time may help to overcome this knowledge gap. Objective: To investigate the relationship of plasma levels of the robust nutritional- and antioxidant defense-related biomarkers carotenoids and tocopherols with both indicators of cognitive and physical performance in persons with mild cognitive impairment (MCI) participating in a structured exercise program. Methods: Data from 40 participants with MCI of the NeuroExercise study were analyzed. Participants had undergone a blood withdrawal for the analysis of plasma concentrations of six carotenoids, two tocopherols and retinol prior to and after one-year of structured exercise. All participants had undergone a broad spectrum of cognitive and physical performance tests. Results: Significant associations between lipophilic micronutrients and cognitive/physical measures were observed that were previously found to play a role in cognitive and physical frailty. In particular, lutein, zeaxanthin, and lycopene are confirmed as robust, reliable, and stable indicators of nutritional defense. Importantly, these micronutrients were associated with cognitive measures prior to the physical training program and to a more prominent extent with indicators of motoric function after the physical exercise program. Conclusion: Specific profiles of lipophilic micronutrients are associated to cognitive performance measures and, especially after a structured exercise program, to indicators of physical performance.

Atrial fibrillation: a geriatric perspective on the 2020 ESC guidelines.

BACKGROUND: The Task Force for the diagnosis and management of atrial fibrillation (AF) of the European Society of Cardiology (ESC) published in 2020 the updated Guidelines for the Diagnosis and Management of Atrial Fibrillation with the contribution of the European Heart Rhythm Association (EHRA) of the ESC and the European Association for Cardiothoracic Surgery (EACTS). METHODS AND RESULTS: In this narrative viewpoint, we approach AF from the perspective of aging medicine and try to provide the readers with information usually neglected in clinical routine, mainly due to the fact that while the large majority of AF patients in real life are older, frail and cognitively impaired, these are mostly excluded from clinical trials, and physicians' attitudes often prevail over standardized algorithms. CONCLUSIONS: On the basis of existing evidence, (1) opportunistic AF screening by pulse palpation or ECG rhythm strip is cost-effective, and (2) whereas advanced chronological age by itself is not a contraindication to AF treatment, a Comprehensive Geriatric Assessment (CGA) including frailty, cognitive impairment, falls and bleeding risk may assist in clinical decision making to provide the best individualized treatment.

Cluster Randomized Controlled Trial on the Effects of 12 Months of Combined Exercise Training during Hemodialysis in Patients with Chronic Kidney Disease-Study Protocol of the Dialysis Training Therapy (DiaTT) Trial.

Patients with chronic kidney disease (CKD) on hemodialysis (HD) experience treatment-related immobility and physical deconditioning, which is responsible for an increased risk of frailty and a high burden of multi-morbidity. Exercise has been shown to counteract this vicious cycle; however, its effectiveness has only been investigated in small cohorts. Therefore, the objective of the Dialysis Training Therapy (DiaTT) trial will be to assess the effects of a 12-month intradialytic exercise program on physical functioning, frailty and health economics in a large cohort of HD patients in a real-world setting. DiaTT will be a prospective, cluster-randomized (1:1), controlled, multi-center, interventional clinical trial across 28 dialysis units, aiming at the recruitment of >1100 CKD patients on HD. The intervention group will receive 12 months' intradialytic exercise (combined aerobic and resistance training), whereas the usual care group will not receive intervention. The primary endpoint will be a change on the sit-to-stand test (STS60) result between baseline and 12 months. Secondary endpoints will include physical functioning, frailty, quality of life, 3-point MACE, hospitalizations, survival, quality of HD, health literacy and health care costs. By including almost as many patients as previously investigated in smaller trials, DiaTT will be the largest randomized, controlled trial assessing frailty, quality of life and mortality in the field of nephrology.

Risk Stratification of Patients Undergoing Percutaneous Repair of Mitral and Tricuspid Valves Using a Multidimensional Geriatric Assessment.

BACKGROUND: Given their advanced age and high comorbidity, individual risk assessment is crucial in patients undergoing transcatheter mitral and tricuspid valve repair. Therefore, we evaluated the use of a comprehensive geriatric assessment score, the multidimensional prognostic index (MPI), for risk stratification in these patients. METHODS: We conducted a prospective, observational single-center study, including 226 patients undergoing percutaneous repair for mitral or tricuspid regurgitation. The MPI was calculated preprocedural and covers 8 domains (activities of daily living, instrumental activities of daily living, mental status, nutrition, risk of pressure ulcers, comorbidity, medication, and marital/cohabitation status). We sought to identify an association of MPI score with procedural outcomes and 6-month mortality. RESULTS: A total of 53.1% of patients were stratified as low risk according to MPI (MPI-1 group), 44.2% as medium risk (MPI-2 group), and 2.7% as high risk (MPI-3 group). Procedural efficacy and safety were similar between groups. The estimated survival rate at 6 months was 97±2% in MPI-1 group, 79±4% in MPI-2 group (hazard ratio, 6.90 [95% CI, 2.36-12.2]; P≤0.001) and 50±20% in MPI-3 group (hazard ratio, 20.3 [95% CI, 4.51-91.3]; P<0.001). An increase in 1 SD of the MPI score (0.14 points, possible range of MPI score 0-1) was associated with a hazard ratio of 2.13 (95% CI, 1.58-2.73; P≤0.001) for death after 6 months. The risk association of the MPI with mortality remained significant in multivariate analysis including risk factors, such as peripheral artery disease and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. CONCLUSIONS: A comprehensive geriatric assessment with the MPI score provides additional information on mortality risk beyond established cardiovascular risk factors.

Nutritional cognitive neuroscience of aging: Focus on carotenoids and cognitive frailty.

The term "nutritional cognitive neuroscience" was recently established to define a research field focusing on the impact of nutrition on cognition and brain health across the life span. In this overview, we summarize the robust evidence on the role of carotenoids as micronutrients with different biological properties in persons with cognitive (pre)frailty. As neurodegenerative processes during aging occur in a continuum from brain aging to dementia, we propose the name "nutritional cognitive neuroscience of aging" to define research on the role of nutrition and micronutrients in cognitive frailty. Further studies are warranted which integrate carotenoid interventions in multidomain, personalized lifestyle strategies.

COVID-19 mortality as a fingerprint of biological age.

Corona virus disease 2019 (COVID-19) is a global emergency able to overwhelm the healthcare capacities worldwide and to affect the older generation especially. When addressing the pathophysiological mechanisms and clinical manifestations of COVID-19, it becomes evident that the disease targets pathways and domains affected by the main aging- and frailty-related pathophysiological changes. A closer analysis of the existing data supports a possible role of biological age rather than chronological age in the prognosis of COVID-19. There is a need for systematic, consequent action of identifying frail (not only older, not only multimorbid, not only symptomatic) persons at risk of poor outcomes.

NeuroExercise: The Effect of a 12-Month Exercise Intervention on Cognition in Mild Cognitive Impairment-A Multicenter Randomized Controlled Trial.

Exercise intervention studies in mild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease (AD), have demonstrated inconsistent yet promising results. Addressing the limitations of previous studies, this trial investigated the effects of a 12-month structured exercise program on the progression of MCI. The NeuroExercise study is a multicenter randomized controlled trial across three European countries (Ireland, Netherlands, Germany). Hundred and eighty-three individuals with amnestic MCI were included and were randomized to a 12-month exercise intervention (3 units of 45 min) of either aerobic exercise (AE; n = 60), stretching and toning exercise (ST; n = 65) or to a non-exercise control group (CG; n = 58). The primary outcome, cognitive performance, was determined by an extensive neuropsychological test battery. For the primary complete case (CC) analyses, between-group differences were analyzed with analysis of covariance under two conditions: (1) the exercise group (EG = combined AE and ST groups) compared to the CG and (2) AE compared to ST. Primary analysis of the full cohort (n = 166, 71.5 years; 51.8% females) revealed no between-group differences in composite cognitive score [mean difference (95% CI)], 0.12 [(-0.03, 0.27), p = 0.13] or in any cognitive domain or quality of life. VO2 peak was significantly higher in the EG compared to the CG after 12 months [-1.76 (-3.39, -0.10), p = 0.04]. Comparing the two intervention groups revealed a higher VO2peak level in the aerobic exercise compared to the stretching and toning group, but no differences for the other outcomes. A 12-month exercise intervention did not change cognitive performance in individuals with amnestic MCI in comparison to a non-exercise CG. An intervention effect on physical fitness was found, which may be an important moderator for long term disease progression and warrants long-term follow-up investigations. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02913053, identifier: NCT02913053.

The prognostic significance of geriatric syndromes and resources.

BACKGROUND: Geriatric syndromes (GS) do not fit into discrete disease categories and are often underdiagnosed in hospitalized older adults. Geriatric resources (GR) are also not routinely collected in clinical settings, although this may potentiate the beneficial effects of clinical decisions. The prognostic relevance of GS and GR has never been systematically evaluated through clinical tools developed for clinical decision purposes. AIM: To ascertain the impact of common GS and GR on patients' prognosis as assessed by means of the comprehensive geriatric assessment (CGA)-based Multidimensional Prognostic Index (MPI). METHODS: One hundred and thirty-five hospitalized patients aged 70 years and older underwent a CGA evaluation with calculation of the MPI on admission and discharge. Accordingly, patients were subdivided in low (MPI-1, score 0-0.33), moderate (MPI-2, score 0.34-0.66), and severe (MPI-3, score 0.67-1)-risk of mortality at 1 month and 1 year. Nine GR and 17 GS were identified and collected accordingly. RESULTS: A lower number of GS and a higher number of GR were shown to be highly significantly correlated with a lower MPI, as well as years of education, grade of care, and number of medications independent of age, sex and number of GS or GR. Underweight and obesity according to the BMI were significantly correlated to higher number of GS. Patients with more GR had a significantly higher chance of being discharged home. CONCLUSIONS: The MPI evaluation together with GS and GR in acute care for older patients should be encouraged to improve clinical decision-making.

Telemedicine-Assisted Self-Management Program for Type 2 Diabetes Patients.

Background: Lifestyle interventions with personalized self-management programs have shown benefits for patients with type 2 diabetes mellitus (T2DM), a devastating highly prevalent disease worldwide. Despite advances in drug therapy and nonpharmacological strategies achieved in the past recent years, self-management programs to be implemented in everyday life are needed. The aim of the present prospective study was to evaluate the effects, in terms of glycated hemoglobin (HbA1c) values and self-management behavior, of a telemedicine-assisted self-management program offered to T2DM patients by a large private health insurance company. Methods: Participants with T2DM included 60 adults in the intervention group (M = 59.4 years) and 55 adults in the control group (M = 58.4 years). In the beginning of the study, the intervention group was provided with a tablet computer, a glucometer, and a step counter. Additionally, they received an individual need-based telephone coaching to address and improve motivation and diabetes self-management in daily life. The control group received care as usual and were not offered additional treatment. The study examined the results of a diabetes lifestyle program after 3 months. Results: The intervention resulted in significantly greater declines in HbA1c compared with the control group. In addition, tele-assisted participants showed significant improvements in Diabetes Self-Management scale score and body mass index compared with usual care participants. Conclusions: Patients with T2DM can benefit from telemedicine-assisted self-management programs, which may offer new options for treatment and prevention of disease progression. More follow-up and research is needed to assess feasibility and effectiveness on a larger scale.