Background: Aging entails a progressive impairment of functions and, ultimately, leads to increased susceptibility to morbidity and mortality. Unsurprisingly, over 85% of people over 75 years old suffer from chronic diseases. Patients with chronic conditions often present a complex interplay of multimorbidity, polypharmacy and frailty, which are influenced by several characteristics of patients, including sex (i.e., biological factors, determined by the sex chromosomes, sex hormones, genetic and epigenetic mechanisms) and gender (i.e., a social construct and refers to culture-bound conventions, roles, and behaviors). Thus, addressing the health needs of the aged population requires the integration of clinical and individual complexity into decision-making processes and organizational flows to pursue an effective implementation of precision medicine, in the quest of improving outcomes for these people.

Aims: The primary objective of the study is to provide a framework to assess the sex and gender effect in aging research, by creating a gender-oriented frailty index (GFI) score, and by developing an artificial intelligence-based tool to make it applicable in clinical practice during and after unplanned hospitalization. As a secondary objective, we will explore the relationship between thrombo-inflammatory status and the GFI.

Methods: To achieve the primary objective, we designed a nationwide observational multicenter study, involving internal medicine and geriatric wards in Italy. Inpatients will be included if they are older than 55 years, and with an estimated life expectancy greater than 12 months. Written informed consent from each participant will be obtained. Frailty will be assessed through several available tools, including the Clinical Frailty Scale, the Frail Scale, the Fried Scale and Rockwood and Mitnitski Frailty Index. Clinical, functional, nutritional and gendered psycho-social data will be collected through specific questionnaires during the in-hospital stay and patients will be followed up to assess the primary outcome defined by the occurrence of death or unplanned hospitalizations over 12 months post-discharge. For the secondary objective (only in recruiting units at Sapienza University, Rome), blood samples will be collected before discharge to characterize the thrombo-inflammatory profile by advanced spectral flow cytometry techniques and microfluidic-based flow studies.

To analyze the collected data we will employ machine learning techniques to construct a bio-psycho-social predictive model using an algorithmic approach, which exploits the provided data to find the relevant features and to combine them to estimate the interaction and cumulative effects of the variable, design a specific and easy-to-measure clinical score, and theoretically to suggest initiatives to implement the management of multilevel complexity of aging people.

On behalf of Working Package 1 Spoke 3 AGE-IT

Background:
Atrial fibrillation (AF) is the most prevalent arrhythmia among older adults and is known to
adversely affect cardiovascular outcomes. However, its long-term impact on functional
abilities—particularly physical performance—is less well understood, especially when considering
the modifying roles of cognitive impairment, frailty, and sex differences. Given the importance of
mobility and strength in maintaining independence in aging populations, understanding how AF
contributes to physical decline is essential for targeted preventive and rehabilitative strategies.
Objective:
To evaluate the longitudinal association between AF and physical performance in older adults,
considering the influence of cognitive status, frailty, and sex differences.
Methods:
This observational cohort study included 2104 individuals aged ≥65 years living in both community
and institutional settings. Baseline assessments collected comprehensive sociodemographic,
clinical, cognitive, functional, and frailty data. Participants were stratified by cognitive function
using the Mini-Mental State Examination (MMSE; cutoff ≥24 vs. <24) and underwent physical
performance tests (handgrip strength, walking speed, and sit-to-stand test) at baseline and after an
average follow-up of 4.4 years. Atrial fibrillation was identified at baseline. Associations between
AF and changes in physical performance were analyzed using multivariate regression and mixed
linear models, with adjustments for frailty and sex.
Results:
At baseline, 149 participants (7.1%) had AF. No significant cross-sectional association was
observed between AF and physical performance measures. Longitudinally, participants with both
AF and cognitive impairment (MMSE<24) experienced a significantly steeper decline in handgrip
strength [-0.05 (95% CI: -0.09; -0.003), p = 0.03] and walking speed [-0.14 (95% CI: -0.23; -0.06),
p = 0.001], with more pronounced effects in females. In cognitively intact individuals (MMSE≥24),
only walking speed declined significantly in the AF group [-0.07 (95% CI: -0.12; -0.01), p = 0.02],
with a similar trend observed among males. These associations remained robust after adjusting for
frailty.
Conclusions:
AF is associated with a decline in physical performance over time, particularly walking speed and
handgrip strength, and these effects vary by cognitive function and sex. Individuals with both AF
and cognitive impairment are especially vulnerable, suggesting a synergistic interaction that may
accelerate physical decline. Sex-specific differences further underscore the need for personalized
risk assessment and management.
Implications:
These findings highlight the importance of integrated care approaches that consider cardiac rhythm
disorders, cognitive health, frailty, and sex in the assessment and prevention of physical decline in
older adults. Future research should explore whether early intervention for AF may help preserve
functional abilities, especially in cognitively frail individuals.

Background

Due to improved medical care and new drugs (CFTR modulators), ageing in Cystic Fibrosis (CF) is becoming more common, and the complexity of the disease and the frailty of awCF increase. This study aimed to assess the main clinical and anamnestic characteristics of adult CF patients and to evaluate the association of frailty with the CF genotyping classification.

Methods

An observational cross-sectional study was conducted at the Adult CF Center in Naples. We enrolled 139 CF adult patients (mean age 32.89 years, 46% F). All patients were assessed by spirometry for respiratory function, by ADL and IADL for functional status, and by the Study of Osteoporotic Fractures (SOF) Index for frailty.

Results

60,4% of the enrolled patients were found to be robust. The pre-frail/frail group was more frequently females (p=0.020), had a lower BMI (p=0.001), worse respiratory function, a higher number of pulmonary exacerbations/years, cycles of antibiotic therapy, and hospitalization (all p < 0.001) with respect to robust patients. The patients included in the pre-frail/frail group take a polypharmacotherapy and were affected by more CF-related diseases (all p < 0.001). The best predictor of the pre-frail/frail status was a low FEV₁ level.

Conclusions

Since CF patients show similarities to pre-frail/frail subjects, CF could be considered an early manifestation of a geriatric syndrome. These results could better define the progression of CF, but above all, they suggest the usefulness of employing some tools used in the management and therapy of frail subjects to identify subjects with more severe CF.

Background

Older adults with physical frailty and sarcopenia (PF&S) are at increased risk for mobility disability. Identifying early predictors of mobility disability is critical to design preventive strategies.

Methods

A secondary analysis was performed using data from the SPRINTT trial (NCT02582138). Participants were community-dwelling older adults with PF&S and no mobility disability at enrolment. The primary outcome was incident mobility disability, defined as the inability to complete a 400-meter walk test within 15 minutes. Participants allocated in the control group (i.e., not engaged in multicomponent intervention) were considered for this analysis to avoid intervention-related confounding. A total of 88 variables collected at baseline and including demographic, clinical, anthropometric, social and laboratory variables were evaluated as candidate predictors. Multivariate classification and machine learning models (including Partial Least-Squares Discriminant Analysis [PLS-DA], Random Forest and Gradient Boosting) were used to identify key predictors of disability over 26 months. Associations were confirmed using Cox proportional hazards models.

Results

Among 759 participants (71.3% women; median age 78 years), 354 (47%) developed mobility disability. The best-performing PLS-DA model achieved 67.6% classification accuracy, which was comparable to machine learning algorithms. Time to complete the 400-meter walk at baseline was the most consistent and important predictor across all models. In multivariate Cox regression, longer 400 m walk time, older age, lower SPPB score, and higher CES-D and SARC-F scores were independently associated with increased risk of mobility disability. Depressive symptoms significantly modified the association between walking time and disability risk (interaction p<0.001). Participants with both slow gait (≥480 s) and elevated depressive symptoms (CES-D ≥9) had the highest risk of developing mobility disability (HR = 2.69; 95% CI: 1.89–3.84). Kaplan-Meier analyses confirmed the additive prognostic value of gait speed and depression on mobility outcomes.

Conclusions:

Slower gait speed and elevated depressive symptoms independently and synergistically increase the risk of mobility disability in older adults with physical frailty and sarcopenia. Simple thresholds such as 480 s for walking time and CES-D ≥9 may support early identification of high-risk individuals and guide preventive interventions.

Anisocytosis, defined as the presence of red blood cells (RBCs) of varying sizes is quantitatively described by the red cell distribution width (RDW), a routinely reported parameter in complete blood counts. While the exact mechanisms linking elevated RDW to increased mortality remain unclear, elevated RDW levels are thought to reflect disrupted erythrocyte homeostasis, potentially due to factors such as oxidative stress, inflammation, malnutrition, dyslipidemia, hypertension, erythropoietin dysfunction, and telomere shortening.

Accumulating evidence suggests that anisocytosis is associated with a wide range of chronic conditions including cardiovascular diseases, venous thromboembolism, cancer, diabetes, respiratory and hepatic diseases, and overall mortality. As such, RDW has been proposed as a potential biomarker for frailty and mortality risk in older populations.

This study investigated the prognostic value of RDW in predicting long-term mortality among a cohort of 2,198 older adults from Southern Italy (including 1,388 community-dwelling individuals and 810 nursing home residents) and a cohort of 4,692 hospitalized older adult in Central Italy. Participants were followed for an average of 12 years. A Cox proportional hazards regression model was used to assess the association between baseline RDW levels and mortality risk, adjusting for age, sex, and functional status as measured by Activities of Daily Living (ADL).

The analysis revealed that higher RDW levels were significantly associated with increased mortality risk over the follow-up period. RDW emerged as a strong and independent predictor of mortality in all settings, suggesting that anisocytosis may serve as a valuable biomarker for long-term survival in aging populations.

Vascular aging is a major contributor to the development of atherosclerotic cardiovascular disease and plays a critical role in the onset and progression of acute coronary syndrome (ACS). Among the molecular hallmarks of vascular aging, telomere attrition has emerged as a key mechanism underlying vascular dysfunction and the pathogenesis of ACS.

This study explored telomere biology in both clinical and in vitro studies to better understand its contribution to ACS risk and vascular senescence. Clinically, peripheral blood samples were analyzed from three patient groups undergoing coronary angiography: 98 patients with ACS, including cases of ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, and unstable angina; 87 patients with stable angina; and 39 patients with normal coronary arteries. Leukocyte telomere length (LTL) was measured using quantitative PCR.

Parallel in vitro experiments were performed on human umbilical vein endothelial cells (HUVECs) exposed to oxidative stress and treated with Astragaloside IV (AS-IV) to investigate telomere dynamics in models of replicative senescence (RS) and stress-induced premature senescence (SIPS).

The results revealed a significant association between reduced LTL, altered expression of telomeric repeat-containing RNA (TERRA), and increased cellular senescence markers in ACS patients. In vitro, cellular stress was shown to accelerate telomere dysfunction, an effect that was mitigated by AS-IV treatment.

Together, the clinical and in vitro findings highlight telomere dysfunction as a contributor to vascular aging and increased ACS risk, emphasizing its potential as a biomarker and therapeutic target in atherosclerotic cardiovascular disease.

Introduction: Intrinsic Capacity (IC) is a novel model proposed by World Health Organization to evaluate the aging process, defined as the composite of all physical and mental capacities that an individual can draw upon throughout life. Muscle Ultrasound (MUS) has been employed to evaluate muscle mass wasting as tool to assess sarcopenia in late life. The present study aims to evaluate the association between IC and MUS measures in a population of hospitalized older adults.

Methods: Patients aged ≥65 years underwent Comprehensive Geriatric Assessment (CGA) for the evaluation of the domains of health and functional status, cognition, nutrition, physical performance. Following standard procedure, a IC z-score was elaborated, taking into account 4 main domains: cognition (through Mini Mental State Evaluation, MMSE), nutrition (by Mini Nutritional Assessment, MNA), vitality (through handgrip strength) and locomotion (by Short Performance Physical Battery, SPPB). Muscle thicknesses (MT) of rectus femoris plus vastus intermedius was measured through MUS axial cross-section. Multivariable regression analysis was employed to determine factors associated with IC.

Results: The study population consisted of 129 older patients, 92 males (71.3%), with mean age of 74.51±7.67 years. Average MT of rectus femoris plus vastus intermedius was 30.91±8.53 mm. At multivariable regression analysis, IC resulted significantly and independently associated with MT.

Conclusion: MT of rectus femoris plus vastus intermedius, measured through MUS, resulted to be significantly related to IC in a population of hospitalized older patients. In the CGA-based assessment of IC, MUS may constitute an additional imaging domain.

Background. Frailty is a significant issue for stroke survivors. Its prevalence ranges from 22.7% to 49.0% (Hanlon et al., 2023, Palmer et al., 2019), and it is associated with adverse outcomes, including increased risk of mortality and hospitalisation (Hanlon et al., 2023). The Short Physical Performance Battery (SPPB) has been found to be a reliable predictor of disability in stroke survivors (Stookey et al., 2014) and it is recommended by the Italian Society of Physical Medicine and Rehabilitation for the routine assessment of persons with previous stroke (Cecchi et al., 2021). Recently, markerless image-based motion analysis has established itself as a suitable alternative of wearables-based motion analysis in research and clinical settings (McGuirk et al., 2022), possibly allowing for a more granular and accurate assessment. Furthermore, devices currently used for rehabilitation enable for both markerless and ground interaction forces (GIF) analysis, allowing for a whole postural-kinematic-kinetic assessment.

This study aims to assess test-retest reliability, criterion validity, and predictive value for incident falls and disability at 6 months of an instrumented (markeless and GIF analysis) version of the SPPB (iSPPB), in persons with chronic stroke.

Methods. This is a prospective observational non-profit study funded by the European Union – NextGeneration EU, project: Aft.it “Ageing well in an ageing society”. Fifty-five consecutive individuals with chronic (>6 month from the event) ischemic/haemorrhagic stroke attending the University-directed S.O. Department of Clinical and Experimental Medicine of the University of Florence – IRCCS Don Carlo Gnocchi (Florence) are being enrolled when matching the following criteria: 65 years or older, lower limb motor component of the Fugl Meyer Assessment (llmFMA) score>35, Mini Mental State Examination (MMSE)<24, absence of clinical instability/physical impairments which do not allow for or contraindicate study procedures; 55 participants guarantee considering a 10% rate of dropouts an “adequate” sample size following COSMIN criteria. At baseline-test (T0), iSPPB and SPPB scores are collected along with: demographic and clinical features (including falls number/outcome in the last year), Timed Up and Go (TUG) test, disability measures (Modified Barthel Index – MBI, Modified Ranking Scale – MRS, Lawton-Brody instrumental Activities of Daily Lining Scale - iADLS), fear of falling (Falls Efficacy Scale – FES), and cognitive/psychological variables (MMSE and Hospital Anxiety and Depression Scale - HADS). At baseline-retest (T1), iSPPB and SPPB scores are collected again by the same rater 2-7 days apart from T0-T1. Finally, at 6 moths follow up (T2), disability (MBI and iADLS), psychological (MMSE), and clinical (numbers and outcome of falls) variables are assessed by phone. Devices used for administering the iSPPB are DWALL and WOLKERVIEW (produced by Tecnobody® - Via Lodi 10, 24044 Dalmine, Bergamo, Italy), for the sit to stand/balance assessment and the 4 meters walk test respectively. Thanks to markerless and GIF analysis, the iSPPB allows to derivate further potentially useful parameters in addition to the three subscales and the overall SPPB scores, namely postural, kinetic, and kinematic parameters (e.g. postural sways by centre of pressure displacement, articular angles, gait speed, and step length). For test-retest reliability of iSPPB derived parameters and subscales/overall scores, the one-way random ANOVA Intraclass Correlation Coefficient for single measures (ICC_1,1) will be computed along with the Standard Error of Measurement – SEM (SD_test-retest×√1-ICC) and the Minimal Detectable Change with 95% confidence - MDC₉₅ (SEM×1.96×√2). To assess the criterion validity of iSPPB subscales/overall scores, correlation between these values and those obtained by SPPB as the reference standard will be computed, using parametric or non-parametric statistics depending on the distribution of the variables. Finaly, correlations between all variables collected at baseline (including iSSPB derived postural, kinetic, and kinematic parameters) and those measuring incident falls and disability at 6 months follow up will be estimated: first separately (univariate analysis) and then considering only significantly-correlated (p<0.05) ones together by a linear/logistic regression model (multivariate analysis), to identify parameters that are independent predictors of incident falls and disability at 6 months.

Results. To date (29 May 2025), 12 individuals (5 man and 7 woman; mean age 77.77±7.33, range 68-96) are enrolled. The number of evaluated participants is inadequate at the moment for obtaining any solid although preliminary data on test-retest reliability, criterion validity, or predictive value of iSPPB scores/derived parameters by statistical analysis, but we plan to complete the enrolment and the analysis by 31 July.

Main implication of the research. Since the paucity of the collected data, to date no conclusions are allowed, but the enrolment proceeds quirkily, and we plan to reach the a priori estimated sample size by the Age.it General Meeting date. So, we will be able to present solid estimates of test-retest reliability and criterion validity of the iSPPB scores/derived parameters, in addition to some preliminary results regarding the predictive value of such postural-kinematic-kinetic parameters for incident falls and disability.

References

● Cecchi F, Cassio A, Lavezzi S, et al. Redefining a minimal assessment protocol for stroke rehabilitation: the new “Protocollo di Minima per l’ICtus” (PMIC2020). Eur J Phys Rehabil Med. 2021;57(5):669-676. doi:10.23736/S1973-9087.21.06638-7.

● Hanlon P, Burton JK, Quinn TJ, Mair FS, McAllister D, Lewsey J, Gallacher KI. Prevalence, measurement, and implications of frailty in stroke survivors: An analysis of three global aging cohorts. Int J Stroke. 2023 Jul;18(6):720-727. doi: 10.1177/17474930231151847. Epub 2023 Jan 30. PMID: 36621981; PMCID: PMC10311928.

● McGuirk TE, Perry ES, Sihanath WB, Riazati S, Patten C. Feasibility of Markerless Motion Capture for Three-Dimensional Gait Assessment in Community Settings. Front Hum Neurosci. 2022 Jun 9;16:867485. doi: 10.3389/fnhum.2022.867485. PMID: 35754772; PMCID: PMC9224754.

● Palmer K, Vetrano DL, Padua L, Romano V, Rivoiro C, Scelfo B, Marengoni A, Bernabei R, Onder G. Frailty Syndromes in Persons With Cerebrovascular Disease: A Systematic Review and Meta-Analysis. Front Neurol. 2019 Nov 29;10:1255. doi: 10.3389/fneur.2019.01255. PMID: 31849819; PMCID: PMC6896936.

● Stookey AD, Katzel LI, Steinbrenner G, Shaughnessy M, Ivey FM. The short physical performance battery as a predictor of functional capacity after stroke. J Stroke Cerebrovasc Dis. 2014 Jan;23(1):130-5. doi: 10.1016/j.jstrokecerebrovasdis.2012.11.003. Epub 2012 Dec 14. PMID: 23253531; PMCID: PMC3786198.