Fight Aging!

The Longevity Escape Velocity Foundation (LEVF) is initially working to assess combinations of approaches to the treatment of aging, to assess the degree to which mouse life span is affected. Aging consists of many distinct mechanisms, and comprehensive rejuvenation will require a diverse package of therapies. Yet the research and development community undertakes little work on combined treatments. Here, the Lifespan.io team talks to Aubrey de Grey about some of the details of the work presently under way.

We are obviously very excited about LEVF's robust mouse rejuvenation (RMR) project. Could you walk our readers through its design and goals?

This is envisioned as a rolling research program aiming to increase both the mean and maximum lifespan of mice by at least 12 months with various combination therapies started late in life. For the first study, four therapies have been chosen: rapamycin, a senolytic, hematopoietic stem cell transplantation (HSCT), and telomerase expression. I believe we'll have two outcomes. One of them scientific, and the other more, if you like, rhetorical. We want to get mice to live a lot longer than they do now: at least a year longer, starting the treatment or treatments only after middle age. The idea is that this will appeal more directly to people who care, vote, pay taxes, and make donations than if you do early-onset interventions. So, I decided to put numbers on this, to have a milestone that clearly says this is where we want to get to. We believe this will be a sufficiently dramatic result.

With such a lofty goal at hand, would you like to make some predictions about the results? For instance, which interventions or combinations are more likely to succeed?

Definitely not. Let's be clear: I do not actually have lofty expectations for this first experiment. We've been saying from the beginning that this is a rolling research program, and our top priority is, as soon as we get this one kicked off, we're going to design the next one, and to bring in the money, which is about three million dollars for each round. So, no, I have no idea what we're going to get with this one, but I'm hoping that we'll be able to do subsequent rounds more than once a year - maybe every nine months or so - because we don't need to wait for the results of the first one to decide how to do the second one. We're also incorporating masses of information from the community, from literature, and we already have a plenty good list of things that we'd like to try in the next round.

Have you decided on what senolytic will be used?

Yes, we just decided on it. We're going to use conjugated navitoclax. As you probably know, navitoclax has a reputation as a reasonably good senolytic. However, it's not very specific. But researchers had this extraordinarily simple and brilliant idea based on the fact that most senescent cells have a high expression of beta-galactosidase. You covalently attach galactose to the molecule in a location that makes the molecule not work. But because it's galactose, if the cell is producing beta-galactosidase, galactose will be cleaved off in senescent cells and only in senescent cells.

What will you be measuring?

We're going to measure all sorts of stuff in addition to lifespan. We will focus heavily on function with tests such as the rotarod, so that we have good information on healthspan. We'll be doing that in different ways. First, we'll have a bunch of non-invasive things that measure agility, visual acuity, physical appearance, including alopecia and kyphosis (the bending of the spine). These are well-established measures of biological age. In addition, we will be sacrificing some mice at various periods during the study and asking what condition they're in. On top of that, we will be looking at mice that die naturally during the experiment and figuring out what they died of. So, we're really covering all the bases.

Link: https://www.lifespan.io/news/aubrey-de-grey-on-levf-and-robust-mouse-rejuvenation/