Rejuvenate Bio Reprogrammed Genes to Double Remaining Life of Old Mice

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Rejuvenate Bio systemically delivered AAVs (gene therapy delivered via altered virus shells), encoding an inducible OSK system, in 124-week-old mice extends the median remaining lifespan by 109% over wild-type controls and enhances several health parameters. Treated mice lived another 18 weeks, on average, while control mice died in nine weeks. This was a doubling of the remaining life from the point of treatment. The treated mice lived about 7% longer overall. This is like taking 77-year-old people and instead of living another 10 or 11 years they lived 20-22 years.

They will need to analyze life-extension effect reported by Rejuvenate could be due to changes in a single organ or group of cells, rather than a general mouse-wide rejuvenation effect. Among other shortfalls in its research, Rejuvenate will need to determine and then publish how many cells were changed by the genetic treatment.

They will next have to show that it works on healthier, younger mice and with dogs. Rejuvenate Bio is targeting de-aging dogs as a potential $70 billion per year business.

Importantly, they observed a significant improvement in frailty scores indicating that they were able to improve the healthspan along with increasing the lifespan. Furthermore, in human keratinocytes expressing exogenous OSK, we observed significant epigenetic markers of age-reversal, suggesting a potential reregulation of genetic networks to a younger, potentially healthier state. Together, these results may have important implications for the development of partial reprogramming interventions to reverse age-associated diseases in the elderly.

Six months ago, Nextbigfuture interviewed Daniel Oliver, the CEO of Rejuvenate Bio.

The world’s population is growing older, with a doubling of the median age from 1900 to 2020, leading to an increased societal burden. Aging is the strongest risk factor for most common human diseases. It is important to identify anti-aging interventions to delay or even potentially reverse the aging process. Increasing longevity has historically referred to extending the ‘lifespan’ of an organism through various interventions such as public health policies, caloric restriction, or through pharmaceutical interventions. One potential pitfall of increasing longevity is that it may not necessarily improve quality of life or healthspan. For example, an organism may live longer but still experience age-related diseases and physiological decline, albeit on a longer timescale. Age reversal, on the other hand, refers to the process of restoring an organism to a younger state, abrogating the effects of aging at the cellular level, and consequently increasing both health span and lifespan.

The other pitfall of longevity research is cycle-time. For assessment and development of potentially efficacious interventions, it would necessitate waiting for the organism to die. Many groups are working to elucidate biomarkers that are sensitive and correlate reliably with increased lifespan, yet the current gold standard remains ‘time to death’. This readout works well for short-lived multicellular model organisms such as C. elegans (∼3 weeks) and D. melanogaster (∼70 days). At the mouse level, testing anti-aging interventions can take 0.5 to 3 years.

Using a cocktail of transcription factors, OCT4 (O), SOX2 (S), KLF4 (K), and c-MYC (M), collectively known as OSKM or Yamanaka factors, seminal studies showed that somatic cells can be reversed to a pluripotent state. Cells outside of the body can be completely de-aged.

Transgenic mouse models are not suitable to enable translation of therapeutic strategies to humans for age reversal, hence they used an AAV system to systemically deliver OSK. Secondly, young humans are not the target population for age-reversal therapeutics. They chose extremely old mice (124 weeks) as a model system for improved translatability. Wild type C57BL6/J mice have a median lifespan of ∼129 weeks, equivalent to ∼80 years in humans.

They drove inducible OSK expression in 124-week mice (∼77 years in human age) using a two part AAV system, where one vector carried a constitutively expressed rtTa and the other vector contained a polycistronic OSK expression cassette driven by doxycycline responsive TRE promoter. They selected AAV9 capsid to ensure maximal distribution to most tissues. They injected 124-week-old WT C57BL6/J mice retro-orbitally (RO) with 100 μl containing either PBS (formulation buffer) or 1E12 vg of each vector for a total dose of ∼6E13 vg/kg.

They are cautiously optimism that a partial rejuvenation therapy can be safely delivered in humans. Prudent and thorough monitoring studies in large animals will be required to assess the safety and efficacy of partial rejuvenation studies.

They envision therapeutic rejuvenation in aging humans, first in specific age-related disease settings and later for therapeutic healthspan and lifespan extension.

18 thoughts on “Rejuvenate Bio Reprogrammed Genes to Double Remaining Life of Old Mice”

  1. ” For assessment and development of potentially efficacious interventions, it would necessitate waiting for the organism to die.” Not at all. You just need to wait for it to live.

    • Instead of typing OSK into google, which is too short and vague, try a more distinctive term like “Yaminaka”

      That takes you to the relevant wikipedia article, and this is exactly the sort of technical nerd subject that wikipedia is very good at. From there we find that you can reduce cells back to the original stem cells using a few reprogramming factors.

      “The original set of reprogramming factors (also dubbed Yamanaka factors) are the transcription factors Oct4 (Pou5f1), Sox2, Klf4 and cMyc. ”

      So, that’s 4 factors, called (for short) O, S, K and M. Different researchers use combinations of these factors. So you get OSK combination. Or SKM combination.

      Seriously, go read the wiki article. It’s a very good intro.

  5. “Wild type C57BL6/J mice have a median lifespan of ∼129 weeks, equivalent to ∼80 years in humans.
    They drove inducible OSK expression in 124-week mice (∼77 years in human age)”
    “124-week-old mice extends the median remaining lifespan by 109% over wild-type controls and enhances several health parameters. Treated mice lived another 18 weeks, on average, while control mice died in nine weeks. This was a doubling of the remaining life from the point of treatment.”

    The numbers show that being a test control mouse conferred an average additional life span of 5 weeks.

    • “The numbers show that being a test control mouse conferred an average additional life span of 5 weeks.”

      Probably the living conditions in this experiment were above average even for the controls. You’d think it’s so well defined (with exact cages, exact food) that there wouldn’t be variation like this, but sometimes you just have a lab tech with better mouse-handling skills. That’s why you always use controls and don’t just compare to historical data.

  6. Impressive. wonder what the limit is to doubling. Give it to a toddler, and they die at 160?
    Glad they are working on dogs, I would love it if dogs could live an extra decade.

    • It’s not working like that. Reprogramming on a toddler is like changing your car parts after a week of driving. Pretty useless and it won’t make your car last longer. It will work best on middle aged (40+) and not much on younger adults (other damage repairing therapies required to rejuvenate a 35 yeard old to a 25 years old)

    • Sadly, for now at least, “. . . young humans are not the target population for age-reversal therapeutics . . .”

      • Dogs are
        1. Much shorter lifespans than humans so it’s much easier to test if your treatments are producing a material effect.
        2. Much cheaper and more legal to experiment on than humans.
        3. Probably don’t have some longevity factors that humans already have, so that’s a couple of low hanging fruit (or at least, not quite as high hanging).
        4. About 1 million times easier to legally start selling medicine for.
        5. Once you’ve got it working on dogs, THEN you’ve got the money and political kudos floating in to push it through to another large mammal.

        And, I’m forced to admit
        6. If it all goes horribly wrong and the dogs start growing tentacles and tearing off heads to eat the brains of mortals so you need to FAE bomb the entire research centre… it’s going to be bad, but nothing like as bad as if these were humans.

    • Smart. They invest a lot of money and maybe get good health — traditionally, you can’t really buy that. Not only are they maybe about to buy it, these are people who really like making money. So they will then be looking to get their money back, and then some, by making it somewhat affordable so they can sell it to the rest of us.

      Bear in mind that even if the cost works out to be the same as one caffeinated fancy drink at Starbucks every day, it will be far beyond the reach of most of the world.

      It seems harsh, but that may be a blessing in that the countries that don’t have below replacement negative birthrates hold most of the people that wouldn’t be able to afford it (outside of China, maybe). On the other hand, the elites in all those countries will get it. Will it create additional problems between the masses and their undying elite? Probably some, but not enough (in most cases) to be a regime changer, if the history of inequality is any guide.

      Still, changes will be necessary in the tax system in many countries. Warren Buffet made his first billion when he was 57. Now, in his 90s, he is worth over 100 billion. Now imagine if he had another century. Estate taxes will probably need to be replaced with inheritance taxes, and those inheritance taxes may have to be steeply graduated (after a very large exclusion) and applied even to the living, when they reach age 100, and every, say, twenty years after that.

      Bad things happen to countries that ignore the rights of the individual, even if it is to subordinate them to the needs of society. But the reverse is also true. Bad things happen to countries that ignore the needs of society, subordinating them to the rights of the individual. Humans and extremes just don’t do well together. Yet so many people are willing and eager to jump behind their chosen cause and push it to ridiculous extremes while, like a pendulum, it will inevitably swing back too far in the other direction.

      • On a warlike economy footing, the whole world could spend about $50k billions each year,
        just for research and treatment.

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