THE BIOLOGY OF AGING
All living organisms must adapt to a changing environment to thrive, or even just to survive. Aging may be defined as the loss of resiliency to adapt to a changing environment leading to physiologic decline and eventually fragility. Cells adapt to their environment by sensing both exogenous and endogenous disturbances, or stresses, and mounting a stress response in an attempt to remediate the stress. Endogenous stress challenges arise out of cellular demand, such as a demand to increase capacity of mitochondrial energy production, to repair DNA damage, and to increase the capacity of cells to fold proteins. Exogenous stressors, such as UV light, infectious agents and pollution, present additional stress challenges. These stress challenges enhance levels of oxidative signaling which mediate key signal transduction pathways in the cellular stress response. Under homeostatic oxidative signaling, the cellular stress response mounts a biological response to remediate the stress and fulfill cellular demand. For example, in the face of genotoxic and proteotoxic stressors, the stress response up-regulates proteins to increase the capacity for DNA repair and protein folding.
In aging, oxidative signaling operates outside a golden mean of homeostasis, and dysregulates the cellular stress response, leaving cells with unresolved stress and unmet cellular demand. Unmet cellular demand begets aging phenotypes, like those characterized by the hallmarks of aging. In our work, we investigated cell survival, loss of proteostasis, genome instability, mitochondrial dysfunction and senescence.
AgeisBio, through its research into the biology of aging, has discovered an endogenous target mechanism to address aging by regulating oxidative signaling. We emulated aging and degenerative disease in cell models by generating phenotypes characterized by chronic up-regulation of stress pathways and down-regulation of cytoprotective pathways. We demonstrated our target mechanism's ability to induce cellular reprogramming, which reverses aging phenotypes and rejuvenates cells. In rejuvenated cells, stress pathways are lowered toward control levels and cytoprotective and rejuvenative proteins are increased, thereby improving overall cellular health [MORE DETAIL]. We're developing rejuvenation therapies that serve as neuroprotectants in neurodegenerative and retinal degenerative diseases.
Figure 1
Figure 1: Representative Plots. hTERT-RPE cells were treated with Redox Stress with or without Drug. qRT-PCR and immunoblot were used to study mRNA and proteins which were then quantified.
Aging phenotypes exhibit chronic activation of stress pathways, including up-regulation of inflammatory, ER stress and DNA damage, and downregulation of cytoprotective proteins, including pro-survival and antioxidant pathways. Target-mediated cellular reprogramming both upregulates cytoprotective proteins (pro-survival, antioxidant, DNA damage response, mitochondrial lifecycle, and autophagic pathways), and downregulates chronic stress pathways.
We also generated aging damage phenotypes including oxidative-stress induced senescence and DNA damage. We demonstrated our target mechanism's ability to reverse aging damage, including reversal of oxidative stress-induced senescence and DNA damage.
Figure 2a
Figure 2b
Figure 2a: Reversal of Age-Induced Senescence, (b) Reversal of Age-Induced DNA Damage Response Pathways. Primary human RPE cells were subject to oxidative and replicative stress to senescence and senescent cells were quantified using β-galactosidase assay. We observed that treatment with our activator reversed oxidative stress-induced senescence in a dose-dependent manner.
Figure 2b: Representative graph showing pattern of changes in mRNA expression for DNA damage marker genes using qRT-PCR in Primary human RPE cells subject to ROS and then treated with our activator. We see an increase in DNA damage response pathway markers suggesting an upregulation of these pathways to repair the damage caused by ROS.