Donations to Important Antiaging Research Doubled in October

Donations from Didier Coeurnelle enable next phase of LEVF (Longevity escape velocity foundation) Robust Mouse Rejuvenation research program.

The initial donation of €200,000 (approximately $220,000) will be increased by a further €200,000 donations to LEVF during the month of October 2024 will be doubled. Donate to LEVF in the next 10 days to boost antiaging research.

These donations enable a key set of pre-study pilots ahead of the next phase of LEVF’s groundbreaking investigations into the effects of combining different damage-repair interventions for middle-aged mice.

RMR1, the first phase of this Robust Mouse Rejuvenation project, has been running since February 2023, and is now nearing completion. Mice in this project have received combinations of up to four different treatments.

Goals and Motivations

As in RMR1, the ambition for RMR2 is to achieve “Robust Mouse Rejuvenation”. We define this as an intervention or treatment program that:

is applied to mice of a strain with a well-documented mean lifespan of at least 30 months

is initiated at around 12 months younger than the mean lifespan

increases both mean and maximum lifespan by at least 12 months

The primary endpoint for the study is to determine the interactions between the various interventions, as revealed by differences between treatment groups (receiving different subsets of the interventions), on overall lifespan.

However, they are also investigating aging and morbidity trajectories, causes of death, and functional decline. In this way they will add greatly to the understanding of which benefits these interventions confer and how they synergize, or possibly antagonize.

The first study extended the lifespan by about 42% or 5 months.

The more detailed analysis, teasing out the relative impact of different treatments, is getting more and more clear and interesting. Here are a few highlights.

I think we have to accept that our senolytic was a bust. We have some theories about why – more on that in due course – but in short we definitely do NOT think senolytics in general are useless, just that there’s still some way to go to extract their full potential.

As I noted in the last update, the impact of the other damage-repair treatments (HSCs and telomerase) over and above rapamycin is disappointingly insignificant in females but looks rather good in males. In fact, at this point it begins to be arguable that the damage-repair treatments actually DIMINISH the benefits of rapa in females – but have the opposite, i.e. beneficial, impact in males. This is definitely something requiring more thought – and, of course, more studies – but first let’s see how things look when RMR1 is complete.

The only-telomerase group is the one with the starkest sex-disparity: bucking the above trend, it was downright bad for male mice but definitely beneficial for females. Was that disparity big enough to survive statistical significance, given how many hypotheses we are testing simultaneously in this study? Watch this space!

Treatment 1 for RMR2- Deuterated polyunsaturated fatty acids

Lipid peroxidation occurs as a consequence of metabolism and plays a significant role in cellular dysfunction with aging. Free radicals strip electrons from membrane lipids in a cascading fashion, generating lipid peroxides and other harmful byproducts which damage DNA and proteins. Membrane integrity and fluidity are disrupted, resulting in impaired membrane transport and intracellular signaling, as well as damaging mitochondria, leading to the production of more free radicals.

Studies have found that this cascade can be inhibited, however, by replacing reactive hydrogens in candidate fatty acids with deuterium atoms, generating deuterated polyunsaturated fatty acids (D-PUFAs). This isotopic reinforcement makes D-PUFAs resistant to reactive oxygen species (ROS)-initiated chain reactions, allowing them to withstand oxidative damage. Furthermore, it has been demonstrated that the presence of even a small fraction of D-PUFAs among natural PUFAs in membranes will effectively inhibit lipid peroxidation, alleviating disease phenotypes several disease models. Several clinical trials utilizing D-PUFAs have been conducted in humans for a diverse range of pathologies, particularly for cognition and memory, and safety is well-established.

Further, D-PUFAs can be provided in animal chow, eliminating unnecessary injections and associated stress on the animals. When consumed, D-PUFAs incorporate into membranes in many tissues, without any reports of toxicity.

Treatment 2 for RMR2- Mouse Serum Albumin

Serum albumin is the most abundant circulating protein in mammalian plasma, accounting for approximately 60% of total blood protein. It has a critical role in maintaining the blood’s osmotic pressure and additionally serves as an important carrier protein for endogenous and exogenous ligands such as fatty acids, metal ions and drugs. It is, however, the third main function of serum albumin we are primarily interested in – that is, its role in the maintenance of intravascular redox homeostasis, a property dependent on the redox state of a free thiol on Cys34. Due to serum albumin’s abundance in plasma, this thiol contributes a large amount of ROS scavenging activity when in its reduced state, and changes in the percentage of reduced vs oxidized serum albumin are indicative in states of liver disease, renal dysfunction, and diabetes mellitus, as well as in aging.

There is promising evidence that repeated administration of physiochemically virgin serum albumin in saline can improve multiple healthspan metrics in aging mice, influencing both mean and maximum lifespan. In addition to bolstering redox buffering capacity, treatment in this way may also confer a plasma-diluting effect, which is known to rejuvenate multiple organs and tissues on its own.

Treatment 3 for RMR2 – MesenChymal Stem Cells

The progressive loss of stem cell regenerative potential remains one of the most obvious consequences of aging and is a primary focus of rejuvenation therapeutics. Thus, therapies to restore stem cell functionality, including stem cell transplant, are promising strategies for longevity medicine. Stem cell aging remains a high-value target for rejuvenation therapeutics, particularly those aiming for a systemic benefit with possible lifespan extension. Therapeutic administration of stem cells is already demonstrated to improve disease and aging phenotypes in animals and in humans and is the focus of ongoing clinical trials.

Although it is believed that the vast majority of systemically administered stem cells are eliminated from the system within a few days of injection, there are still significant and much longer-lasting physiological changes which result from body’s response to cell injections. It seems likely that the benefits of MSC therapy are via the ability of administered cells to induce changes in resident cells, promoting the switch to a regenerative phenotype, which further rejuvenates cells and tissues downstream.

Our first RMR study (RMR1) also included youthful stem cells as an intervention, however with some key differences, mainly in that it utilized lineage-depleted bone marrow stem cells (HSCs) isolated from young mice. While HSCs populate the cells of the blood and immune system, MSCs constitute an important part of the BM microenvironment that houses HSCs. In addition, the MSC lineage gives rise to many tissues including bone, fat, muscle, and cartilage, as well as endodermal and ectodermal tissues such as neurons, blood vessels, skin, and cells of the liver, pancreas, heart. MSCs can be derived from a variety of sources and can be reliably expanded ex vivo, permitting their use at scale and under repeat-dosing conditions.

Treatment 4 for RMR2 – Partial cellular reprogramming

Partial reprogramming involves the temporary activation of a set of genes known as the Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc), which can induce a state of cellular rejuvenation without altering the cell’s original identity. This approach addresses the aging process at the cellular level, potentially complementing other interventions and providing a comprehensive strategy for age-related therapies.

The Yamanaka factors work by rewiring the cellular epigenome, erasing certain age-associated epigenetic marks and activating genes associated with youthful characteristics. This leads to functional rejuvenation in various tissues such as the kidney, skin, liver, and muscle, enhancing tissue health and restoring the regenerative capacity of aged cells, potentially slowing down age-related decline. Further, by reducing the expression of genes involved in inflammation, senescence, and stress response pathways, partial reprogramming may delay the onset and progression of age-related diseases which contribute significantly to mortality and reduced quality of life in aging individuals.

Partial reprogramming has thus attracted substantial interest in recent years both from a research and investment standpoint. Achieving efficient and safe delivery of reprogramming factors to specific cells or tissues in vivo, however, still presents a considerable challenge and the development of practical, targeted, and cost-effective delivery methods is vital for successful application. The delivery of these factors has historically been achieved using viral vectors or genetic modifications, however recent innovations have focused on liposome-mediated delivery as mRNA, and even chemical induction of reprogramming factors using reagents and small molecules.