Leader: Maria Grano (UNIBA); Other collaborator(s):
We plan to investigate the mechanisms underlying the age-related diseases osteoporosis and sarcopenia in relevant animal models and to identify and validate new therapeutic targets that can be used to promote anabolic responses in bone and skeletal muscle as anti-aging agents.
Brief description of the activities and of the intermediate results
Main policy, industrial and scientific implications
Our results revealed that prolonged systemic treatment with irisin in aged mice improved memory and spatial cognitive abilities, mimicking exercise-induced effects, by increasing the expression of neuroplasticity factors and activity of the FNDC5/irisin system mainly in the hippocampus. Moreover, our results demonstrated that irisin is effective in increasing bone mass and inhibiting muscle fiber degeneration. These findings provide the first evidence for the possibility of using the therapeutic treatment with irisin for age-related cognitive and musculoskeletal decline.
To evaluate the potential role of irisin as a biomarker of osteosarcopenia and neurodegeneration in age-related diseases, we collected cerebrospinal fluid (CSF) and plasma samples from patients with diagnosis of Alzheimer dementia (AD, n=82), mild cognitive impairment (MCI, n=44), and subjective memory complaint (SMC, n=20).
We quantified irisin levels by ELISA assays and we correlated these results with clinical and fluid AD biomarkers. We observed that CSF irisin was reduced in AD patients, with lower levels in females. Moreover, CSF irisin correlated positively with Aβ42 in both female and male patients, and negatively with CDR-SOB only in females. A negative trend was also observed between CSF irisin and t-tau levels in all patients and in the female subgroup.
In parallel, we conducted other studies in mouse model of depression, osteoporosis, and bone disease associated to multiple myeloma.
DISSEMINATION
Two oral contributions selected for the Age-It General Meeting. Ca' Foscari Venice, May 20-22, 2024:
Two poster contributions selected for International Meetings:
To evaluate the potential role of irisin as a biomarker of neurodegeneration in age-related diseases, we measured plasma irisin levels in patients with Parkinson’s disease (PD, n=82) and healthy controls (HD, n=89) matched for age and sex, and we correlated the results of this analysis with PD clinical variables. We observed that PD patients had significantly lower plasma irisin levels compared to HC. Moreover, a significant correlation between memory functions and plasma irisin levels was observed in PD patients. The results of this study have been submitted to the Journal “npj Parkinson's Disease” for publication. In parallel, we conducted other studies in a mouse model of cardiac hypertrophy and fibrosis, two age-related changes that may occur in the ageing heart.
Main policy, industrial and scientific implications
Our results in PD patients suggest that plasma irisin may reflect disease-related processes in PD. Moreover, we demonstrated that treatment with systemic irisin prevents cardiac hypertrophy and fibrosis in a mouse model of cardiac hypertrophy.
To investigate the association of irisin with cognition in a cohort of dementia patients, we collected cerebrospinal fluid (CSF) and serum samples from patients with diagnosis of Alzheimer dementia (AD, n=82), mild cognitive impairment (MCI, n=44), and subjective memory complaint (SMC, n=20). We quantified irisin levels by ELISA assays and we correlated these results with multi-domain cognition and psychometric tests scores. We observed that CSF and serum irisin levels were reduced in AD and MCI patients compared to SMC. Both CSF and serum irisin positively correlated with global cognitive efficiency, along with specific cognitive domains. Higher levels of CSF and serum irisin were associated with better cognitive performance. The results of this study have been submitted to the Journal “Alzheimer's & Dementia” for publication. In parallel, we explored the direct effect of recombinant irisin treatment on proliferation and invasion in in vitro models of metastatic melanoma cell lines.
Main policy, industrial and scientific implications
Our results showed the key involvement of irisin in cognition, indicating its potential role as a cognitive biomarker of AD progression.
To evaluate the potential role of sclerostin, an osteokine primarily secreted by mature osteocytes, as a biomarker of Alzheimer’s disease (AD), we measured sclerostin levels in the cerebrospinal fluid (CSF) obtained from patients with diagnosis of dementia due to AD (n=82), mild cognitive impairment (MCI, n=44), and subjective memory complaint (SMC, n=20) by ELISA assays, and we correlated these results with AD biomarkers, amyloid beta (Aβ) 42, phosphorylated tau (p-tau), and total tau (t-tau), and clinical parameters of dementia severity. We observed that CSF sclerostin increased in patients with dementia due to AD and correlated negatively with Aβ42 and positively with p-tau, t-tau, and dementia severity. The results of this study have been submitted to the Journal “Alzheimer's & Dementia” for publication.
In parallel in vitro studies, we explored the effect of recombinant irisin treatment on myoblasts, osteoblasts, osteocytes in a simulated microgravity model.
Main policy, industrial and scientific implications
Our results are of great clinical relevance for the identification of sclerostin as a promising biomarker in early AD stages showing the association of CSF sclerostin with Aβ42, tau pathology, and dementia severity in the early disease stages
DISSEMINATION
Two poster contributions selected for the 6° World Conference on Psychology and Behavioral Science, Londra, July 14-15, 2025:
Two poster contributions selected for the Congresso Nazionale SIPF "The Adaptive Brain", Verona, September 17-19, 2025:
To investigate the potential role of sclerostin, an osteokine secreted by mature osteocytes as a biomarker of cognitive decline in Alzheimer’s disease (AD), we correlated cerebrospinal fluid (CSF) sclerostin levels with domain-specific cognitive scores derived from an extensive standardized neuropsychological battery in a cohort of individuals with biological evidence of AD pathology, including patients with dementia due to AD, mild cognitive impairment (MCI), and subjective memory complaint (SMC). We found a correlation between CSF sclerostin levels and overall cognitive function, as well as with all cognitive domains impaired in AD (i.e., memory, executive function, attention, visuospatial abilities, and language). In addition, in the subgroup of MCI patients, high CSF sclerostin levels were associated with worse overall and domain-specific neurocognitive performance. The results of this study have been submitted to the Journal “Alzheimer's & Dementia” for publication.
DISSEMINATION
Two oral contributions selected for the 1st International Congress “Human in motion”, Portoroz (Slovenia), September 28-October 1, 2025:
One poster contribution selected for the II General Meeting Age-It, Napoli, October 29-31, 2025:
One oral contribution selected for the XXV Congresso Nazionale della Società Italiana dell'Osteoporosi del Metabolismo Minerale e delle Malattie dello Scheletro (SIOMMMS), Siena, December 13-15, 2025:
Three poster contributions selected for the XXV Congresso Nazionale della Società Italiana dell'Osteoporosi del Metabolismo Minerale e delle Malattie dello Scheletro (SIOMMMS), Siena, December 13-15, 2025:
Main policy, industrial and scientific implications
Our results evidenced the negative impact of sclerostin on all the cognitive domains predominantly in prodromal AD, suggesting its potential role as a biomarker of cognitive decline in the early stages of the disease.
Dissemination
Two oral contributions selected for the XXIV Convegno ed Assemblea dei Docenti di Istologia ed Embriologia Umana February 19-23, 2025:
1) Loading-related changes affect FNDC5/Irisin in the musculoskeletal system;
2) Cortical bone loss and fragility precedes amyloid deposition in a triple transgenic mouse model of Alzheimer’s disease.