Most programs aiming to produce therapies that treat aging involve some form of manipulation of cellular metabolism, usually via small molecules initially derived from screens that showed effects on function or survival in lower animals. Effect sizes are usually modest, and decrease relative to species life span as species life span increases; large increases in function and life span in a nematode worm translate to modest gains in a mouse. Where we have the ability to compare mice and humans, in the matter of growth hormone metabolism and calorie restriction, we know that sizable gains in mice do not translate to sizable gains in humans.
Researchers, particularly Brian Kennedy's team, have shown that most combinations of this sort of intervention fail to be useful. Any two marginally positive age-slowing changes to metabolism are far more likely to interfere with one another than they are to combine for a greater effect. Yet aging is a combination of forms of cell and tissue damage, and thus multiple treatments will be needed to address aging. To combine therapies is a desirable end goal, but it must be pursued rationally, using combinations made up of therapies that specifically address different forms of age-related damage. In principle, such combinations should be far less likely to interfere in one another's operation, and the outcome for health and longevity more likely to be additive and greater than any one therapy alone.
This view of combined therapies as the end goal was always implicit in the Strategies for Engineered Negligible Senescence (SENS) view of aging and how to go about the construction of rejuvenation therapies. One must repair the damage, and thus one must combine different repair strategies that address different forms of damage. This is the central point that the Longevity Escape Velocity (LEV) Foundation is attempting to demonstrate in their large, long-running mouse studies. The goal is to pick sensible combinations of therapies based on a damage repair philosophy, and show that these combinations can be additive. Nothing is ever straightforward, and there are clearly things to be learned along the way, but so far the LEV Foundation seems to be proving their point, a useful counterbalance to the work of Brian Kennedy.
Robust Mouse Rejuvenation: Breaking the Ceiling of Longevity Research
For decades, the field of biogerontology has largely focused on a single strategy: manipulating metabolism to slow down the rate at which we age. While approaches like caloric restriction have produced fascinating results in short-lived organisms like worms and flies, they have shown clear limits in mammals. At LEV Foundation, we are pursuing a distinct alternative: maintenance through damage repair. All age-related damage can be classified into a manageable number of categories. Since there are different types of damage, a single therapeutic intervention is insufficient. To achieve meaningful rejuvenation, we must move from isolation to synergy.
This necessity is the foundation of the Robust Mouse Rejuvenation (RMR) programme. We define RMR as a specific engineering benchmark: a multi-component intervention that increases both mean and maximum lifespan in mice by at least 12 months. This must be achieved in a mouse strain with a well-documented mean lifespan of at least 30 months, with treatment initiating only at the advanced age of 18 months. To hit this target, the RMR programme consists of large-scale studies designed to determine how leading-edge interventions behave when deployed together.
The RMR1 study served as a first test, operating at an unprecedented scale with 1000 middle-aged mice divided into 10 subgroups per sex. This granular design allowed us to map the complex web of interactions. We selected four interventions that had individually shown promise in extending mouse lifespan: rapamycin, senolytics, telomerase gene therapy, and hematopoietic stem cell transplantation. By administering these simultaneously, we sought to establish whether their combined impact could finally break through the lifespan ceiling that no single intervention has ever managed to overcome.
The overarching conclusion following the completion of RMR1 is a qualified win for synergy. RMR1 successfully demonstrated that combining damage-repair interventions with metabolic modulation (rapamycin) yields additive benefits. Specifically, we observed a distinct rectangularisation of the survival curve. This means that we significantly increased mean lifespan by ensuring more mice survived into late life. However, we must be clear about the limits of this result. We did not observe a radical extension of maximum lifespan (the age of the oldest survivors). While the all-four combination group outperformed both the naive and mock controls, the "robust" goal of shifting the entire mortality window remains the target for future iterations.
RMR1 demonstrated that a single dose of damage repair has a limited window of efficacy. The damage re-accumulates. Future protocols must likely incorporate repeated dosing for interventions like senolytics and gene therapy. However, the male data revealed that combinatorial treatments extend this window significantly when supported by metabolic stability. We have used these critical lessons to design RMR2. The new study replaces the single-dose approach with cyclic treatments using mesenchymal stem cells and an expanded panel of eight interventions. With the blueprint for this next phase complete, funding is the only remaining bottleneck.
View the full article at FightAging
