Thursday, December 22, 2022
The earlier the better, recent research suggests.
Cells have the ability to self-repair and rejuvenate to a healthier state, at any age. Research in area of human aging and cellular reprogramming is more and more clear on this. The cells may just need input of reprogramming information, at regular intervals - the earlier the better.
Cellular reprogramming has once again been reaffirmed by a new scientific study in the journal of Aging Cell (Alle et. al. 2022). In one of our recent blogs, we discussed the 3 key previous studies (Stanford University, Harvard University and the Salk Institute for Biological Studies) that showed in vitro and in vivo that mammalian cells have the capacity to rejuvenate.
A new study published in the journal of Aging Cell reconfirms that cellular reprogramming can occur with exposure to pluripotent signals. It also points at a very unique feature of rejuvenation: a one-time early exposure to pluripotent reprogramming factors, in early youth, may confer long term cellular rejuvenation benefits to biological processes, strengthening regenerative capacity from a young age.
What is cellular rejuvenation?
Mature cells accumulate damage over time. This is due to various physiological mechanisms responding to the daily wear and tear — the DNA damage, telomere attrition, senescence, protein folding mistakes, epigenetic dysregulation, stem cell depletion and so on. At the DNA level, aging causes accumulation of epigenetic errors that eventually lead to faulty somatic gene expression. If given the right building blocks, scientists have shown that we can repair a lot of this accumulated damage in aged cells.
How do we measure rejuvenation?
Rejuvenation can be measured via the epigenetic clock approach (as opposed to our regular chronological clocks that measure time). Epigenetic aging is biological aging, and in human tissues it can be measured with epigenetic clock measures which assess DNA methylation age of different cell types and tissue types (ex:DNAmAge Clock). Age-related changes of normal tissues are accompanied by quantifiable changes in DNA methylation with age. Changes in DNA methylation in identifiable genomic regions is associated with cellular senescence, chronic disease, neurodegenerative disorders and so on. Age-associated DNAm patterns and age-associated DNAm changes, age-associated methylation sites in genomic regions are points of key measures for biological aging and epigenetic aging at this time.
What is cellular reprogramming?
In scientific literature, cellular rejuvenation is referred to as 'cellular reprogramming' or 'epigenetic reprogramming' or 'nuclear reprogramming'. The reprogramming event occurs in the cell, alters epigenetic markers and somatic gene expression. When scientists expose cells to pluripotent reprogramming factors (via embryonic cells, embryonic stem cells, Yamanaka factors, OSKM), in pulsing bursts, mature cells tend to rejuvenate. Since the process of reprogramming is partial, cellular identities (somatic cells) remain intact, meaning a skin cell remains a skin cell, it's simply functioning as a younger skin cell.
How is cellular reprogramming achieved in the clinical setting?
In regenerative medicine clinical settings, the reprogramming effect we see in literature can be translated into action by giving daily pulsing doses of pluripotent stem cells via IV, in repeated short bursts, over 1-5 weeks. At Stemaid Institute we have found that such protocol design, supported by other IVs (peptides, NAD+, chelation, ozone) is very beneficial. A new study published in November 2022 is adding some new information that may improve the breadth of these programs. New approaches to rejuvenation are always considered.
A new cellular reprogramming study
In a recent study published in the journal Aging Cell, scientists looked at the rejuvenative effects of pluripotent factors on heterozygous half-progeroid mice (a model of premature aging). This mouse type normally accumulates age-related diseases much faster than normal, average lifespan being 35 weeks (1/3 of normal). In previously discussed studies, mice were pulsed with doses of doxycycline, turning OSKM expression on and off. In this study, the researchers took a different approach. They continuously added a small dose of the drug to the drinking water, essentially using a constant dose over lifetime. Not only were the treatment group mice healthier than controls, but they also lived longer, extending median age of death from 42.6 - 55.6 weeks. A continuous lifelong treatment with smaller doses of 0.2 mg/ml of doxycycline yielded almost the same results as the more conventional larger doses 1 mg/ml pulsed period treatment. This effect is of course not easily reproducible in clinical settings with adult human populations. They cannot practically be on continuous treatment. But it is very interesting to keep in mind for future development.
A surprising new finding
However, there was another intriguing finding that may be interesting clinically. When the researchers tried limiting the treatment to a period of 2.5 weeks early in life, they still observed lifespan extension with a medium dose of 0.5 mg/ml. The increase in maximum lifespan was even more significant than with the lifelong treatment (66.1 weeks). The single treatment early in life resulted in noticeable improvements in fitness, higher ratios of lean mass to fat (healthy body mass), improved strength tests, improved turgor and elasticity of the skin, less fibrosis in lungs, spleen, kidneys, and improved bone mass and cartilage volume. This astounding result may indicate that pluripotent treatment may be beneficial at early age, and may confer lifelong benefit. Despite the small sample size, this effect is important to keep in mind when deciding how early to start pluripotent rejuvenation regimens.
How early should we start Pluripotent Stem Cell Therapy?
This recent mouse study suggests 'the earlier the better'. When Pluripotent Yamanaka factors were activated just once in a young heterozygous progeroid mouse model, as explained above, the reprogramming benefits in extending lifespan lasted their lifetime. The early epigenetic reprogramming induced by the treatment improved methylation age, showing that early life treatment may be protective against age-related changed in methylation. The study authors suggest that early application of the reprogramming factors can potentially confer a long term benefit from early age, and be even more effective than if higher dose periodic therapy is applied later in life.
1. A single short reprogramming early in life initiates and propagates an epigenetically related mechanism improving fitness and promoting an increased healthy lifespan - PubMed
2. In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming - PubMed
3. Reprogramming to recover youthful epigenetic information and restore vision - PubMed
4. Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells - PubMed