Short-term pharmacological intervention that increase lifespan and healthspan in aging mice
Rapamycin is a macrolide drug that inhibits cell growth and proliferation. The drug is already approved for use in human patients to prevent transplant rejection and to treat certain tumors. A major breakthrough in aging research has been the discovery that rapamycin also increases lifespan in multiple species and reduces the symptoms and progression of several age-related diseases in rodents and other model organisms. In particular, rapamycin can increase lifespan in rodents even when started late in life, when fed continuously.
Continuous rapamycin administration may not be an appropriate treatment for aging in healthy humans, because of potential negative side effects. Adequate compliance may also be a concern, since healthy individuals may not have the incentive to maintain a rigorous treatment schedule.
We are investigating whether using high doses of rapamycin for a short period of time can increase lifespan and healthspan to a similar, if not greater extent than continuous treatment.
Pharmacological interventions for the treatment of Leigh Syndrome
Leigh Syndrome is a pediatric disease that affects 1 in 40000 newborns. Disease progression is characterized by a rapid loss of organ function, especially skeletal muscle, brain, heart, and lungs. At the moment there is no available treatment for Leigh Syndrome and prognosis remains extremely poor in most cases, with death occurring a few years after diagnosis.
Leigh Syndrome is caused by mutations that impair the mitochondrial electron transport chain and oxidative phosphorylation, the main energetic pathway in living organisms. Recently, our laboratory has discovered that rapamycin can greatly extend lifespan and reduce the symptoms of disease in a mouse model of Leigh Syndrome, characterized by a loss-of-function mutation in Ndufs4, a nuclear gene encoding for a subunit of mitochondrial Complex I. Importantly, rapamycin did not rescue the reduction in oxidative phosphorylation and electron transport chain activity in ndufs4 mice. Instead, rapamycin seems to alter the activity of several metabolic pathways in these mice, reducing glycolytic intermediates and favoring the utilization of fatty and amino acids as energy sources.
We are currently investigating other interventions that can alter metabolism similarly to rapamycin as therapeutic strategies for the ndufs4 mice and ultimately Leigh Syndrome.
Protein aggregation in aging yeast
Loss of protein homeostasis and protein aggregation is a hallmark of aging and age-related diseases. Using the yeast S. cerevisiae, we are investigating the dynamics of aggregation and toxicity of several proteins involved in neurodegenerative and age-related diseases in an aging context. Using yeast’s genetics and well established aging protocols (chronological and replicative lifespan), we hope to uncover the relationship between aging, loss of protein homeostasis, and protein aggregation. In addition, we hope to determine whether age-delaying interventions have a direct impact on the dynamics of aggregation and the toxicity of these proteins. Our initial efforts will focus on alpha-synuclein and TDP-43, two proteins involved in Parkinson’s Disease and Amyotrophic Lateral Sclerosis respectively.
Ph.D. Molecular Pathobiology, Drexel University College of Medicine
M.S. Biotecnologie Industriali, Indirizzo Farmaco-Genomico, Universita' degli Studi Milano-Bicocca
B.S. Biotecnologie, Universita' degli Studi Milano-Bicocca
Rejuvenation: it's in our blood. Bitto A, Kaeberlein M. Cell Metab. 2014 Jul 1;20(1):2-4. doi: 10.1016/j.cmet.2014.06.007.
P62/SQSTM1 at the interface of aging, autophagy, and disease. Bitto A, Lerner CA, Nacarelli T, Crowe E, Torres C, Sell C. Age (Dordr). 2014 Jun;36(3):9626. doi: 10.1007/s11357-014-9626-3. Epub 2014 Feb 21
Reduced mTOR activity facilitates mitochondrial retrograde signaling and increases lifespan in normal human fibroblasts. Lerner C.*, Bitto A.*, Pulliam D., Nacarelli N., Konigsberg M., Van Remmen H., Torres C., Sell C. Aging Cell. 2013 Jun 24. doi: 10.1111/acel.12122.
*: denotes equal contribution