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Background and Purpose FM19G11 up-regulates mammalian target of rapamycin ( mTOR)/hypoxia inducible factor-1α ( HIF-1α) and PI3K/ Akt pathways, which are involved in endothelial function. We evaluated the effects of FM19G11 on defective endothelial vasodilatation in arteries from rats and humans and investigated the mechanisms involved. Experimental Approach Effects of chronic in vivo administration of FM19G11 on aortic endothelial vasodilatation were evaluated together with ex vivo treatment in aortic and mesenteric arteries from control and insulin-resistant rats ( IRR). Its effects on vasodilator responses of penile arteries ( HPRAs) and corpus cavernosum ( HCC) from men with vasculogenic erectile dysfunction ( ED) (model of human endothelial dysfunction) were also evaluated. Vascular expression of phosphorylated-endothelial NOS ( p-eNOS), phosphorylated- Akt ( p-Akt) and HIF-1α was determined by immunodetection and cGMP by elisa. Key Results Chronic administration of FM19G11 reversed the impaired endothelial vasodilatation in IRR. E x vivo treatment with FM19G11 also significantly improved endothelium-dependent vasodilatation in aorta and mesenteric arteries from IRR. These effects were accompanied by the restoration of p-eNOS and cGMP levels in IRR aorta and were prevented by either NOS or PI3K inhibition. p-Akt and p-eNOS contents were increased by FM19G11 in aortic endothelium of IRR. FM19G11-induced restoration of endothelial vasodilatation was unaffected by mTOR/HIF-1α inhibitors. FM19G11 also restored endothelial vasodilatation in HPRA and HCC from ED patients. Conclusions and Implications Stimulation of the PI3K/ Akt/ eNOS pathway by FM19G11 alleviates impaired NO-mediated endothelial vasodilatation in rat and human arteries independently of mTOR/ HIF-1α activation. This pharmacological strategy could be beneficial for managing pathological conditions associated with endothelial dysfunction, such as ED. [ABSTRACT FROM AUTHOR]

The present study was carried out to investigate the effect of Curacron (profenofos), Sumicidin (fenvalerate) and Dimilin (di‐fluobenzuron) on the in vitro rate of protein and RNA synthesis by rabbit liver and muscle tissues. The synthesis of protein and RNA were significantly stimulated in the liver and inhibited in the muscle by graded doses of these insecticides. Profenofos showed maximum effect on protein synthesis in both tissues at a dose of 0.2 μg/mL, while the maximum effect on RNA synthesis occurred at 0.2 μg/mL in the liver and at 2 μg/mL in the muscle. Fenvalerate caused maximum stimulation in both liver protein and RNA synthesis at a dose of 2 μg/mL, and maximum inhibition in the muscle at 10 and 0.2 μg/mL for protein and RNA synthesis respectively. The maximum effect of Dimilin on both tissues was reached at 5 μg/mL for protein synthesis and at 0.2 μg/mL for RNA synthesis. The effect of Dimilin on RNA synthesis was more pronounced in both tissues than its effect on protein synthesis, but this trend was reversed in the case of profenofos and fenvalerate. Present data also showed antagonism between these insecticides on the rate of protein and RNA synthesis. [ABSTRACT FROM PUBLISHER]

Objectives: Insulin resistance determined by Homeostasis Model of Insulin Resistance (HOMA-IR) has been associated with functional decline in non-diabetic older subjects. However, insulin is not routinely assessed. The study evaluated the predictive value of non-insulin-dependent IR surrogates on functional decline in non-diabetic older men and women., Design and Participants: Prospective cohort study over 5 years. The study included 615 older participants from the Toledo Study of Healthy Aging., Methods: Frailty was assessed by the Frailty Trait Scale-5 (FTS-5) at baseline and after 5 years follow-up. 193 subjects experienced functional decline (2.5-point reduction in the FTS-5 score). Multivariate regression models analysed the effect of five described IR surrogates on functional decline considering potential confounders., Results: Among evaluated IR proxies, triglyceride glucose-body mass index (TyG-BMI) and HOMA-IR were significantly associated with an increased risk of functional decline (odd ratio (95% confidence interval) TyG-BMI: 1.16 (1.05, 1.28), p = 0.0035 and HOMA-IR: 1.59 (1.15, 2.21), p = 0.0056) among all participants. When stratified by gender, HOMA-IR was related to functional decline in men [2.02 (1.13, 3.59), p = 0.0173] and TyG-BMI in women [1.19 (1.05, 1.35), p = 0.0057]., Conclusions: Only TyG-BMI index mimics the predictive capacity of insulin-based IR marker. The predictive ability of IR indexes is gender-specific, being TyG-BMI the only index able to predict functional decline in women and HOMA-IR in men., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Several biomarkers have been proposed to identify frailty, a multisystemic age-related syndrome. However, the complex pathophysiology and the absence of a consensus on a comprehensive and universal definition make it challenging to pinpoint a singular biomarker or set of biomarkers that conclusively characterize frailty. This review delves into the main laboratory biomarkers, placing special emphasis on those associated with various pathways closely tied to the frailty condition, such as inflammation, oxidative stress, mitochondrial dysfunction, metabolic and endocrine alterations and microRNA. Additionally, we provide a summary of different clinical biomarkers encompassing different tools that have been proposed to assess frailty. We further address various imaging biomarkers such as Dual Energy X-ray Absorptiometry, Bioelectrical Impedance analysis, Computed Tomography and Magnetic Resonance Imaging, Ultrasound and D3 Creatine dilution. Intervention to treat frailty, including non-pharmacological ones, especially those involving physical exercise and nutrition, and pharmacological interventions, that include those targeting specific mechanisms such as myostatin inhibitors, insulin sensitizer metformin and with special relevance for hormonal treatments are mentioned. We further address the levels of different biomarkers in monitoring the potential positive effects of some of these interventions. Despite the availability of numerous biomarkers, their performance and usefulness in the clinical arena are far from being satisfactory. Considering the multicausality of frailty, there is an increasing need to assess the role of sets of biomarkers and the combination between laboratory, clinical and image biomarkers, in terms of sensitivity, specificity and predictive values for the diagnosis and prognosis of the different outcomes of frailty to improve detection and monitoring of older people with frailty or at risk of developing it, being this a need in the everyday clinical practice., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Erectile dysfunction (ED) is a frequent and difficult-to-treat condition in diabetic men. Protein kinase C (PKC) is involved in diabetes-related vascular and cavernosal alterations. We aimed to evaluate the role of PKC in endothelial dysfunction and NO/cGMP impairment associated with diabetic ED in the human corpus cavernosum (CC) and penile resistance arteries (PRAs) and the potential mechanisms involved. Functional responses were determined in the CC and PRAs in patients with non-diabetic ED and diabetic ED undergoing penile prosthesis insertion. PKC activator 12,13-phorbol-dibutyrate (PDBu) impaired endothelial relaxations and cGMP generation in response to acetylcholine in the CC from non-diabetic ED. PDBu also impaired responses to a PDE5 inhibitor, sildenafil, in non-diabetic ED patients. Conversely, a PKC inhibitor, GF109203X, improved endothelial, neurogenic, and PDE5-inhibitor-induced relaxations and cGMP generation only in the CC in diabetic ED patients. Endothelial and PDE5-inhibitor-induced vasodilations of PRAs were potentiated only in diabetes. Improvements in endothelial function in diabetes were also achieved with a specific inhibitor of the PKCβ2 isoform or an NADPH-oxidase inhibitor, apocynin, which prevented PDBu-induced impairment in non-diabetic patients. PKC inhibition counteracted NO/cGMP impairment and endothelial dysfunction in diabetes-related ED, potentially improving response to PDE5 inhibition.

Objective: To assess the potential role of body composition in the association of insulin resistance (IR) with functional decline and mortality in nondiabetic older persons., Design: Longitudinal population-based cohort of community-dwelling people from Toledo, Spain, aged 65 years or older., Setting and Participants: A total of 1114 nondiabetic persons from the Toledo Study of Healthy Aging cohort (mean age: 74.5, 56.10% female) with complete data at baseline were included. Only 914 participants had fully assessment of functional evaluation during the follow-up period., Methods: IR was determined by the homeostasis model assessment index (HOMA-IR) at baseline while frailty was assessed by the Frailty Trait Scale-5 (FTS-5) at baseline and after 2.99 years' median follow-up period. A total of 319 participants experienced functional decline (2.5-point reduction in the FTS-5 score). A total of 143 deaths were recorded (6.31 years median follow-up) from the Spanish National Death Index. Body compositions were determined using dual-energy x-ray absorptiometry. Multivariate regression models analyzed the effect of HOMA-IR on outcomes, with age, sex, Charlson index, and number of medications included in the basic adjustment model., Results: A 1-logaritmic unit increment in HOMA-IR increased the risk of functional decline after basic adjustment [odds ratio (95% confidence interval): 1.41 (1.09-1.83), P = .009]. This significant association was lost when further adjusted for total fat mass [1.14 (0.86-1.50)] and trunk fat mass [1.03 (0.77-1.37)], which accounted for 62.92% and 91.49% of the association. HOMA-IR was inversely associated with mortality risk [hazard ratio 0.66 (0.49-0.87), P = .0037], an association lost after adjustment for total fat mass [0.74 (0.55-1.01)] and trunk fat mass [0.80 (0.58-1.09)], accounting for 29.05% and 45.78% of the association. Adjustment by lean mass did not modify any of the associations., Conclusions and Implications: Body fat mass, especially in the trunk region, mediates the association of IR with functional decline and to a lesser extent with reduced risk of mortality in nondiabetic older subjects., Competing Interests: Disclosure The authors declare no conflicts of interest., (Copyright © 2023 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Vascular territories display heterogeneous sensitivity to the impacts of aging. The relevance of the STIM/Orai system to vascular function depends on the vascular bed. We aimed to evaluate the contribution of the STIM/Orai system to aging-related vascular dysfunction in rat coronary circulation. Vascular function was evaluated according to myography in coronary arteries from young (three-month-old) and older (twenty-month-old) rats. The effects of aging and STIM/Orai inhibition on the contraction and relaxation of the coronary arteries and on the protein expression of STIM-1, Orai1, and Orai3 in these vessels were determined. Aging-related hypercontractility to serotonin and endothelin-1 in arteries from male rats was reversed by STIM/Orai inhibition with YM-58483 or by specifically blocking the Orai1 channel with Synta66. The inhibitory effects of Synta66 on coronary vasoconstriction were also observed in older female rats. YM-58483 relaxed serotonin- but not KCl-contracted arteries from males. STIM/Orai inhibition improved defective endothelial vasodilations in aged arteries, even in the presence of NO synthase and cyclooxygenase inhibitors, but not in KCl-contracted segments. YM-58483 significantly enhanced relaxations to calcium-activated potassium channel stimulation in aged vessels. Increased protein expression of Orai1 and Orai3 was detected in arterial homogenates and sections from older rats. Upregulation of the Orai channel contributes to aging-related coronary dysfunction, revealing a potential target in reducing CVD risk.

Background: Arterial stiffness leads to several adverse events in the older population, but there is a lack of data on its association with frailty, disability, and mortality in the same population., Objectives: The purpose of this study was to evaluate the role of arterial stiffness in the loss of functional ability (frailty and disability) and mortality., Methods: Data were taken from community-dwelling aged 65 years participants without diabetes in the Toledo Study of Healthy Ageing cohort. Pulse wave velocity (PWV), assessed through SphygmoCor, was recorded at baseline. Median follow-up time were 2.99 years for frailty (frailty phenotype [FP] and Frailty Trait Scale-5 [FTS5]) and disability (Katz Index) and 6.2 for mortality. Logistic regressions models were built for disability and frailty and Cox proportional hazards model for death, adjusted by age and sex, comorbidity, cardiovascular risk factors, asymmetric dimethylarginine levels, and polypharmacy., Results: Overall, 978 (mean age 74.5 ± 5.6 years, 56.7% female) participants were included. Different cut-off points were shown for each outcome. PWV >11.5 m/s was cross-sectionally associated with frailty (FP: OR fully-adjusted model: 1.69, 95% CI: 1.45-1.97; FTS5: OR: 1.51, 95% CI: 1.22-1.87) and disability (OR: 1.51, 95% CI: 1.26-1.79); PWV >10 m/s with incident frailty by FP (OR: 1.36, 95% CI: 1.10-1.68) and FTS5 (OR: 1.40, 95% CI: 1.12-1.75), and PWV >11 m/s with death (HR: 1.28, 95% CI: 1.09-1.50). For incident (OR: 1.28, 95% CI: 1.06-1.55) and worsening disability (OR: 1.21, 95% CI: 1.02-1.45) the threshold was 12.5 m/s. Below these cut-off points, age was the best predictor of adverse outcomes., Conclusions: Arterial stiffness predicts frailty, disability, and mortality in older people, with different cut-off points, ie,severity degrees, for each of the assessed outcomes., Competing Interests: Financial support for this analysis was provided by Abbott. TSHA research was funded by grants from the Spanish 10.13039/501100010198Ministry of Economy, Industry and Competitiveness, cofinanced by the 10.13039/501100008530European Regional Development Funds (10.13039/501100004587Instituto de Salud Carlos III, PI20/00977) and the Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable (CB16/10/00464); the MITOFUN Project, Fundación Francisco Soria Melguizo (Section 2/2020); 10.13039/501100010767Innovative Medicines Initiative Joint Undertaking under grant agreement n◦115621, resources of which are composed of financial contribution from the European Union’ 10.13039/100011102Seventh Framework Programme (FP7/2007-2013) and EFPIA companies. Drs Rueda, Pereira, Sulo are employees of Abbott. Dr Rodríguez-Mañas has received funds as a speaker in Abbott-supported conferences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Background: Stromal interaction molecule (STIM)/Orai calcium entry system appears to have a role in erectile dysfunction (ED) pathophysiology but its specific contribution to diabetic ED was not elucidated., Aim: To evaluate STIM/Orai inhibition on functional alterations associated with diabetic ED in rat and human penile tissues and on in vivo erectile responses in diabetic rats., Methods: Rat corpus cavernosum (RCC) strips from nondiabetic (No DM) and streptozotocin-induced diabetic (DM) rats and human penile resistance arteries (HPRA) and corpus cavernosum (HCC) from ED patients undergoing penile prosthesis insertion were functionally evaluated in organ chambers and wire myographs. Erectile function in vivo in rats was assessed by intracavernosal pressure (ICP) responses to cavernous nerve electrical stimulation (CNES). Expression of STIM/Orai elements in HCC was determined by immunofluorescence and immunoblot., Main Outcome Measures: Functional responses in RCC, HCC and HPRA and STIM/Orai protein expression in HCC. In vivo erectile responses to CNES., Results: Inhibition of Orai channels with YM-58483 (20 µM) significantly reduced adrenergic contractions in RCC but more effectively in DM. Thromboxane-induced and neurogenic contractions were reduced by STIM/Orai inhibition while defective endothelial, neurogenic and PDE5 inhibitor-induced relaxations were enhanced by YM-58483 (10 µM) in RCC from DM rats. In vivo, YM-58483 caused erections and attenuated diabetes-related impairment of erectile responses. YM-58483 potentiated the effects of PDE5 inhibition. In human tissues, STIM/Orai inhibition depressed adrenergic and thromboxane-induced contractions in ED patients more effectively in those with type 2 diabetes. Diabetes was associated with increased expression of Orai1 and Orai3 in ED patients., Clinical Translation: Targeting STIM/Orai to alleviate diabetes-related functional alterations of penile vascular tissue could improve erectile function and potentiate therapeutic effects of PDE5 inhibitors in diabetic ED., Strengths and Limitations: Improving effects of STIM/Orai inhibition on diabetes-related functional impairment was evidenced in vitro and in vivo in an animal model and validated in human tissues from ED patients. Functional findings were complemented with expression results. Main limitation was low numbers of human experiments due to limited human tissue availability., Conclusions: STIM/Orai inhibition alleviated alterations of functional responses in vitro and improved erectile responses in vivo in diabetic rats, potentiating the effects of PDE5 inhibition. STIM/Orai inhibition was validated as a target to modulate functional alterations of human penile vascular tissue in diabetic ED where Orai1 and Orai3 channels were upregulated. STIM/Orai inhibition could be a potential therapeutic strategy to overcome poor response to conventional ED therapy in diabetic patients. Sevilleja-Ortiz A, El Assar M, García-Gómez B, et al. STIM/Orai Inhibition as a Strategy for Alleviating Diabetic Erectile Dysfunction Through Modulation of Rat and Human Penile Tissue Contractility and in vivo Potentiation of Erectile Responses. J Sex Med 2022;19:1733-1749., (Copyright © 2022 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

The impact of aging on vascular function is heterogeneous depending on the vascular territories. Calcium regulation plays a key role in vascular function and has been implicated in aging-related hypercontractility of corpus cavernosum. We aimed to evaluate stromal interaction molecule (STIM)/Orai system involvement in aging-related vascular alterations in the human macro and microvasculature. Aortae specimens and mesenteric arteries (MA), obtained from 45 organ donors, were functionally evaluated in organ chambers and wire myographs. Subjects were divided into groups either younger or older than 65-years old. The expressions of STIM-1, Orai1, and Orai3 were determined by immunofluorescence in the aorta and MA, and by Western blot in the aorta homogenates. The inhibition of STIM/Orai with YM-58483 (20 μM) reversed adrenergic hypercontractility in MA from older subjects but did not modify aging-related hypercontractility in the aortic strips. Aging was related to an increased expression of Orai1 in human aorta, while Orai1 and STIM-1 were upregulated in MA. STIM-1 and Orai1 protein expressions were inversely correlated to endothelial function in MA. Circulating levels of Orai1 were correlated with the inflammatory factor TNF-α and with the endothelial dysfunction marker asymmetric dimethylarginine. Aging is associated with an increased expression of the STIM/Orai system in human vessels with functional relevance only in the microvascular territory, suggesting its role in aging-related microvascular dysfunction.

Functional status is considered the main determinant of healthy aging. Impairment in skeletal muscle and the cardiovascular system, two interrelated systems, results in compromised functional status in aging. Increased oxidative stress and inflammation in older subjects constitute the background for skeletal muscle and cardiovascular system alterations. Aged skeletal muscle mass and strength impairment is related to anabolic resistance, mitochondrial dysfunction, increased oxidative stress and inflammation as well as a reduced antioxidant response and myokine profile. Arterial stiffness and endothelial function stand out as the main cardiovascular alterations related to aging, where increased systemic and vascular oxidative stress and inflammation play a key role. Physical activity and exercise training arise as modifiable determinants of functional outcomes in older persons. Exercise enhances antioxidant response, decreases age-related oxidative stress and pro-inflammatory signals, and promotes the activation of anabolic and mitochondrial biogenesis pathways in skeletal muscle. Additionally, exercise improves endothelial function and arterial stiffness by reducing inflammatory and oxidative damage signaling in vascular tissue together with an increase in antioxidant enzymes and nitric oxide availability, globally promoting functional performance and healthy aging. This review focuses on the role of oxidative stress and inflammation in aged musculoskeletal and vascular systems and how physical activity/exercise influences functional status in the elderly.

Insulin signalling declines with increasing age and impacts skeletal muscle function and longevity in animal models. Our aim was to assess the relationships between insulin resistance (IR) and frailty and mortality in a unique community-dwelling cohort of older people. 991 non-diabetic subjects from the Toledo Study of Healthy Ageing (TSHA) cohort were included. IR was estimated by the homeostasis model assessment index (HOMA-IR) at baseline while frailty was determined by frailty phenotype (FP) and Frailty Trait Scale (FTS) at baseline and after 5-year follow-up. Deaths were also determined. Multivariate regression models were used to analyze the effects of HOMA-IR on outcomes. Age, gender, BMI, education level, cardio- and cerebro-vascular disease, glomerular filtration rate, and disability were included as potential confounding variables in progressive adjustment models. IR determined as increasing log HOMA-IR was inversely associated with risk of mortality. The association remained significant for all adjustment models (HR: 0.64-0.69). When we analyzed survival curves, the higher the HOMA-IR tertile, the lower the mortality rate (highest vs lowest tertile, p = 0.0082). In contrast, IR increased the risk of incident frailty determined by FP (OR 1.81 [1.14-2.87]) as well as deterioration of frailty status determined by worsening in FTS score (OR 1.28 [1.01-1.63]) at 5-year follow-up. In non-diabetic older subjects, IR significantly increases the risk for frailty and functional decline but decreased the risk of death at 5-year follow-up. This finding raises the need of assessing the effect of biomarkers on different outcomes before establishing their role as biomarkers of aging., (© 2021. American Aging Association.)

The role of STIM/Orai calcium entry system on vascular ageing has not been elucidated. We aimed to evaluate the influence of ageing on STIM/Orai signalling and its role on ageing-induced alterations of contractile function in rat corpus cavernosum (RCC) and human penile resistance arteries (HPRA) and corpus cavernosum (HCC). RCC was obtained from 3 months-old and 20 months-old animals. HPRA and HCC were obtained from organ donors of varied ages without history of erectile dysfunction. Aging was associated with enhanced norepinephrine (NE)- and thromboxane analogue (U46619)-induced contractions in RCC which were significantly inhibited by the STIM/Orai inhibitor, YM-58483 (20 μM). Other STIM/Orai inhibitor, 2-aminoethyldiphenylborate also reduced NE-induced contractions in RCC from aged rats. YM-58483 significantly reduced neurogenic contractions and potentiated neurogenic relaxations in RCC from aged rats. In HCC and HPRA, NE-induced contractions were significantly enhanced in older subjects (>65 years-old) but YM-58483 completely reversed ageing-related hypercontractility. Ageing did not modify STIM-1 and Orai1 protein expressions but Orai3 was significantly overexpressed in cavernosal tissue from old rats and older subjects. Contribution of STIM/Orai to cavernosal contraction increases with ageing together with increased expression of Orai3. Orai inhibition could be a potential therapeutic strategy to reduce ageing-related impact on vascular/erectile function., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aging impairs vascular function, but the mechanisms involved are unknown. The aim of this study was to analyze whether aging-related hyperphosphatemia is implied in this effect by elucidating the role of oxidative stress. C57BL6 mice that were aged 5 months (young) and 24 months (old), receiving a standard (0.6%) or low-phosphate (0.2%) diet, were used. Isolated mesenteric arteries from old mice showed diminished endothelium-dependent vascular relaxation by the down-regulation of NOS3 expression, increased inflammation and increased fibrosis in isolated aortas, compared to those isolated from young mice. In parallel, increased Nox4 expression and reduced Nrf2, Sod2-Mn and Gpx1 were found in the aortas from old mice, resulting in oxidant/antioxidant imbalance. The low-phosphate diet improved vascular function and oxidant/antioxidant balance in old mice. Mechanisms were analyzed in endothelial (EC) and vascular smooth muscle cells (SMCs) treated with the phosphate donor ß-glycerophosphate (BGP). In EC, BGP increased Nox4 expression and ROS production, which reduced NOS3 expression via NFκB. BGP also increased inflammation in EC. In SMC, BGP increased Collagen I and fibronectin expression by priming ROS production and NFκB activity. In conclusion, hyperphosphatemia reduced endothelium-dependent vascular relaxation and increased inflammation and vascular fibrosis through an impairment of oxidant/antioxidant balance in old mice. A low-phosphate diet achieved improvements in the vascular function in old mice.

Frailty is considered a clinical marker of functional ageing. Telomere length (TL) has been proposed as a biomarker of biological age but its role in human ageing is controversial. The main aim of the study was to evaluate the longitudinal association of TL with incident frailty and mortality in two cohorts of Spanish community-dwelling older adults. TL was determined at baseline in blood samples from older adults included in Toledo Study for Healthy Aging and ENRICA cohorts while frailty was determined by frailty phenotype (FP) at baseline and at follow-up (3.5 years). Deaths occurring during follow-up were also recorded. Associations of TL with frailty and mortality were analysed by logistic regression with progressive adjustment. Data were separately analysed in the two cohorts and in all subjects by performing a meta-analysis. TL was not different between frail and non-frail subjects. Longer telomeres were not associated with lower risk of prevalent frailty. Similarly, TL at baseline failed to predict incident frailty (OR: 1.04 [0.88-1.23]) or even the development of a new FP criterion (OR: 0.97 [0.90-1.05]) at follow-up. Lack of association was also observed when analysing the development of specific FP criteria. Finally, while frailty at baseline was significantly associated with higher risk of death at follow-up (OR: 4.08 [1.97-8.43], p < 0.001), TL did not significantly change the mortality risk (OR: 1.05 [0.94-1.16]). Results show that TL does not predict incident frailty or mortality in older adults. This suggests that TL is not a reliable biomarker of functional age.