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.
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.
Brian Wang is a Futurist Thought Leader and a popular Science blogger with 1 million readers per month. His blog Nextbigfuture.com is ranked #1 Science News Blog. It covers many disruptive technology and trends including Space, Robotics, Artificial Intelligence, Medicine, Anti-aging Biotechnology, and Nanotechnology.
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