Leader: Mauro Provinciali (UNIPD); Other collaborator(s):
We plan to study the effect of therapies targeted to telomeres and senecent cells in geriatric mice that may reduce the burden of telomere dysfunction during aging. .We will apply non-invasive procedures to measure clinical, physical, cognitive, respiratory and cardiac health during the lifespan of old and geriatric mice. The effects of the interventions will be investigated based on specific frailty and health indexes referred to each functional area. This study will determine whether new senolytics and targeted therapies aimed at correcting telomeric dysfunctions are capable of improving the health of aged mice and identifying which functional areas (physical, cognitive, respiratory or cardiovascular) are most impacted by these treatments.
Brief description of the activities and the intermediate results:
1) We have successfully obtained approval from the Ministry of Health and the Italian National Institute of Health for the first longitudinal study on aged mice targeting telomeric damage (Approval No. 70/2023-PR, Prot. 8502E.24). A total of 250 animals, aged 26 months, were recruited, and each individual is being evaluated monthly for clinical frailty and physical activity and every three months for respiratory, cognitive, and cardiac functions. Blood samples were collected pre-treatment and two months after the start of treatment, separated into plasma and pellet aliquots, and stored at -80°C for subsequent analyses. A subset of animals underwent organ explantation, and the samples were stored under liquid nitrogen for future investigations in our biobank. The longitudinal study is still ongoing.
2) We have also planned two additional longitudinal studies, ensuring the necessary time intervals to optimize the workload.
3) Planning and preparation of the ethical documentation to start the second longitudinal study involving a combined treatment with a senolytic and the probiotic Akkermansia. The project will start in May 2024. Milestone Achieved: Approval obtained from the Ministry of Health and the Italian National Institute of Health (Istituto Superiore di Sanità) for the second longitudinal study (Approval No. 59/2024-PR, Prot. 8502E.27).
Additionally, we have initiated a collaboration with Dr. Vincenzo Lettera from UNICAL (Spoke 2, WP4) through the exchange of biological material stored in our biobank. Plasma samples from young adult and elderly mice will be used to perform proteomic analysis focusing on membrane- related proteins in whole blood cells.
Brief description of the activities and the intermediate results:
The first longitudinal study targeting telomeric damage in aged mice (Approval No. 70/2023-PR, Prot. 8502E.24) is still ongoing. Analysis of the stored organs revealed reduced β-galactosidase (βGal) staining, a marker of senescent cells, in the colon and ileum of treated animals. No variations were observed in other organs (i.e. the spleen, lungs, liver, pancreas, kidneys, heart, skeletal muscle, and brain)
2) A total of 250 aged mice (26 months old) were recruited for the second longitudinal study involving a combined treatment with a senolytic and the probiotic Akkermansia (Approval No. 59/2024-PR, Prot. 8502E.27). Pre-treatment evaluations of clinical frailty, physical performance, and cognitive, cardiac, and respiratory functions have been completed.
Additionally, we have initiated a collaboration with Dr. Vincenzo Lettera from UNICAL (Spoke 2, WP4) to test the in vitro senolytic effect of a recombinant MnSOD.
Brief description of the activities and the intermediate results:
1. The experimental activities related to the first longitudinal study with therapy targeting telomeric damage have been successfully completed. The study showed no evidence of acute or long-term toxicity. Positive outcomes were observed exclusively in female mice, including increased survival, improved clinical frailty index, and enhanced physical performance.
2. The second longitudinal study involving a senolytic and the probiotic Akkermansia is still ongoing. Treatments have begun, and blood and fecal samples were collected both pre-treatment and post-treatment. A subset of animals was sacrificed three months after the start of treatment, and their organs were collected and stored in our biobank for future analyses.
3. Planning and preparation of the ethical documentation for the third longitudinal study. This study will evaluate the therapy targeting telomeric damage in adult animals aged 18 months. The project is scheduled to start in March 2025.
Additionally, we have initiated a collaboration with Dr. Antonio Frigeri from UNIBA (Spoke 2, WP2) through the exchange of biological material stored in our biobank. Brain samples from young and elderly animals will be used to evaluate the involvement of the different Aquaporin-4 (AQP4) isoforms in the aging mechanism.
Brief description of the activities and the intermediate results:
- Malavolta M. Anti-aging interventions in geriatric mice: insights into the timing of treatment, benefits, and limitations. Geroscience. 2024 Aug 8. doi: 10.1007/s11357-024-01309-7.
- Giuliani ME, Bigossi G, Lai G, Marcozzi S, Brunetti D, Malavolta M. Marine Compounds and Age-Related Diseases: The Path from Pre-Clinical Research to Approved Drugs for the Treatment of Cardiovascular Diseases and Diabetes. Mar Drugs. 2024 May 3;22(5):210. doi:10.3390/md22050210.
- Marcozzi S, Bigossi G, Giuliani ME, Lai G, …, Malavolta M. A novel Cognitive Frailty Index for Geriatric Mice. Under revision.
- Bigossi G, Marcozzi S, Giuliani ME, Lai G, …, Malavolta M. A Comparative Analysis of Grip Strength Evaluation Methods in a Large Cohort of Aged Mice. In preparation.
- Cacciatore G, Lettera V, Aiello D, Malavolta M, Marcozzi S, Bigossi G, Amoresano A, Napoli A. Differential proteomics approach to investigate human aging. SOCIETÀ CHIMICA ITALIANA CONGRESSO CONGIUNTO SEZIONI SICILIA E CALABRIA 2024
- Oral communication to the PNRR-Age-it internal meeting in Venice, by Marcozzi Serena