Details on the LEV Foundation's First Study of Combined Interventions in Mice
The recently launched Longevity Escape Velocity (LEV) Foundation will, initially at least, focus on testing combinations of interventions. This work is informed by the SENS view of aging, in that degenerative aging is produced by a limited number of forms of cell and tissue damage that result from the normal operation of metabolism. These include the accumulation of senescent cells, cross-linking of the extracellular matrix, mitochondrial DNA damage, and so forth. Each form of damage produces its own contribution to a complex web of interacting downstream consequences, so while repairing any one form of damage should be beneficial, repairing more than one should be better.
Unfortunately the research and development communities operate under incentives that strongly discourage earnest work on combinations of therapies, these incentives largely resulting from the way in which intellectual property and regulation of medical development interact. Research into combined therapies is necessary to achieve the end goal of a comprehensive toolkit of rejuvenation therapies, but it is near entirely ignored as an aspect of this area of medical research. Thus philanthropic efforts are required to fill in the gap and light the way. Combined interventions are on the roadmap of the rejuvenome project, for example. And now they are a focus at the LEV Foundation.
Robust Mouse Rejuvenation - Study 1
LEV Foundation's flagship research program is a sequence of large mouse lifespan studies, each involving the administration of (various subsets of) at least four interventions that have, individually, shown promise in others' hands in extending mean and maximum mouse lifespan and healthspan. We focus on interventions that have shown efficacy when begun only after the mice have reached half their typical life expectancy, and mostly on those that specifically repair some category of accumulating, eventually pathogenic, molecular or cellular damage. The first study in this program is starting in January 2023.
Our ultimate goal in this program is to achieve "Robust Mouse Rejuvenation". We define this as an intervention, almost certainly multi-component, that: (a) is applied to mice of a strain with a historic mean lifespan of at least 30 months; (b) is initiated at an age of at least 18 months; (c) increases both mean and maximum lifespan by at least 12 months.
In each study in this program, we will examine the synergy of (typically at least four) interventions already known individually to extend mouse lifespan when started in mid-life. We will determine not only the ultimate readout of lifespan, but also the interactions between the various interventions, as revealed by the differences between the treatment groups (receiving different subsets of the interventions) in respect of the trajectories with age of cause of death, decline in different functions, etc. In this way we will add greatly to the understanding of which benefits these interventions confer and how they synergize, or possibly antagonize.
There are two key motivations for this program. One is purely biomedical: as with all mouse work with a biomedical end goal, we hope to generate data that will inform the development of therapies to let humans live longer in good health. The other could be called rhetorical, societal, political - it is to demonstrate a definitive proof of concept that aging is much more malleable than society currently insists on thinking it is, and thus must be viewed as a tractable medical problem, rather than a fact of life.
Interventions are chosen on the basis that they 1) act systemically and 2) have individually shown some lifespan-extending effect in naturally aged mice. In this way, we are specifically selecting rejuvenation therapeutics, as opposed to those which are purely preventative and/or require early life intervention. Therapies are also selected to have minimal mechanistic overlap, based on our current understanding of their mechanisms of action. The first four interventions selected for the initial study are rapamycin, hematopoietic stem cell transplant, telomerase upregulation via TERT gene therapy, and senolytic treatment.