We are improving DNA sequencing to achieve our goal of turning biology into an information science. Along the way, various SENS approaches will be accelerated by improved DNA sequencing, and we present here specific experimental paths for using the tool in service of SENS. As one example, sequencing offers extreme technical shortcuts in molecular directed evolution techniques, allowing larger populations to be interrogated with fewer rounds of evolution and increased stringency of selection. This will accelerate attempts to find, improve, or evolve enzymes and other catalysts targeting age-related molecular damage. As another example, sequencing will enable better quality control of stem cells in both clinical and laboratory settings. We will discuss these specific experimental strategies and others that leverage improved sequencing to hasten progress toward saving lives via SENS therapy approaches.
Insulin-like growth factor I (IGF-I) is a powerful neurotrophic molecule which appears to be part of the physiologic self-repair mechanisms of the adult brain. Using the aging female rat as a model of age-related dopaminergic (DA) neurodegeneration, we have implemented short-term restorative IGF-I gene therapy in the hypothalamus and cerebral ventricles. Short-term (17 days) intrahypothalamic IGF-I gene therapy achieved a nearly full restoration of hypothalamic DA neuron function as determined by morphometric analysis and by correction of the chronic hyperprolactinemia that typically develops in senescent (28-30 mo.) female rats as a consequence of hypothalamic DA neuron dysfunction. Short-term intracerebroventricular (ICV) IGF-I gene therapy was able to ameliorate motor performance in senescent females which typically show a marked decline in motor function as compared to young (2 mo.) counterparts. Although our and others’ studies reveal that IGF-I has a high restorative potential in the aging brain, up to now the only way to administer the therapeutic vectors is via stereotaxic injections in the target brain areas. The invasiveness of this procedure significantly limits its eventual implementation in human patients. The association of viral vector-based gene delivery with nanotechnology now offers the possibility of developing minimally invasive gene therapy strategies for the brain. This approach combines Magnetic Drug Targeting (MDT) and magnetofection, two novel methodologies based on the use of magnetic nanoparticles (MNP). The goal of MDT is to concentrate magnetically responsive therapeutic complexes in target areas of the body by means of external magnetic fields. Magnetofection is a methodology developed in the early 2000’s by Christian Plank’s group, in Munich, Germany. It is based on the association of MNP with nonviral or viral vectors in order to optimize gene delivery in the presence of a magnetic field. Thus, the German group could develop magnetic nanoparticle formulations that improve considerably the efficiency of adenovirally-mediated gene delivery. Based on the capabilities of the above technologies we have undertaken to develop, in collaboration with the German team, minimally invasive IGF-I gene delivery to the brain. This will be achieved by ICV administration of MNP-viral vector complexes at distal sites and magnetic trapping of the complexes at the target brain region by means of a properly focused external magnetic field. The progress of these studies will be discussed. The long-term goal of our endeavor is to use this technology to implement minimally invasive gene therapy in Alzheimer and Parkinson patients as well as in other neurological pathologies amenable to gene therapy intervention.
The loss of skeletal muscle is one of the most dramatic changes in the human body consequent to advancing age and is referred to as sarcopenia. It is a primary cause of age-related changes in muscle performance, functional status and metabolic homeostasis. In an effort to counter sarcopenia and its consequences, we have studied strategies to inhibit the muscle-enriched TGF-β superfamily member, myostatin. The purpose of this seminar is to demonstrate how antibody-directed approaches to myostatin have not only increased muscle mass in mouse models of aging and disease, but improved physical function and whole-body metabolism. Ultimately, strategies to disrupt myostatin may provide a means to extend healthspan.