The present study explored for the first time the blood-based proteomic signature that could potentially distinguish older adults with and without cognitive frailty (CF). The participants were recruited under the Malaysian Elders Longitudinal Research (MELoR) study. Cognition and physical frailty were determined using the Montreal Cognitive Assessment (MoCA) and Fried's criteria, respectively. The differential protein expression in the blood samples (38 CF vs 40 robust) were then determined using the Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH) analysis. A total of 294 proteins were found to be differentially expressed in the CF group as opposed to the robust group. Considering proteins with fold change (FC) ≥ ± 2 and p-values 78%, specificity > 75%, accuracy > 80% and area under the curve (AUC) > 0.8. The major biological pathways that could be potentially dysregulated by the nine proteins were associated with lipid metabolism and the retinoid system. The present findings warrant further validation in future studies that involve a larger cohort.
Neurovascular ageing is a major contributor to cerebrovascular vulnerability and poor stroke outcomes in older adults. Progressive deterioration of the neurovascular unit (NVU), driven by oxidative stress, neurovascular coupling dysfunction, blood-brain barrier (BBB) disruption, inflammageing, cellular senescence, mitochondrial dysfunction, and impaired autophagy compromises neurovascular resilience and increases susceptibility to ischemic injury. Among the molecular pathways implicated in these processes, Sonic hedgehog (Shh) signaling and matrix metalloproteinases (MMPs) are important regulators of neurovascular remodeling, BBB integrity, and post-stroke recovery. Although these pathways have largely been investigated independently, emerging evidence suggests potential bidirectional interactions between Shh signaling and MMP activity. In particular, Shh/Gli1 signaling has been associated with regulation of MMP-2 and MMP-9 in experimental models, whereas MMP-2 can disrupt SCUBE2, an extracellular regulator of Shh ligand presentation, providing a potential mechanism for reciprocal pathway modulation. This review examines the Shh-MMP axis as a potential mechanistic link between neurovascular ageing and ischemic vulnerability, integrating current evidence to evaluate how dysregulation of these pathways may contribute to BBB dysfunction, extracellular matrix remodeling, neuroinflammation, and impaired neurovascular repair. We further discuss the potential therapeutic implications of modulating the Shh-MMP axis to preserve neurovascular resilience and improve cerebrovascular outcomes in the ageing brain, while highlighting the importance of temporal and cell-specific targeting.
This research examines the replicability and generalizability of the association between purpose in life and grip strength. An individual-participant meta-analysis of 27 samples (total N=115,972) from 24 countries that spanned four continents (Asia, Europe, North and South America) with self-reported purpose in life and dynamometer-assessed grip strength. Purpose in life was associated with stronger grip strength in every sample and aggregated in a random-effects meta-analysis (meta-analytic estimate=.06, p