The New Science of Aging: Winding Back the Body Clock
Human age reversal has jumped from pure science fiction to research reality. Until very recently, the idea of age reversal and rejuvenation in humans was not a topic discussed in serious scientific circles. The idea was, at best, highly speculative. At worst it was the stuff of charlatans and snake oil salesmen.
Within the past 5 years, this picture has radically changed. Mainstream science is now seriously investigating the possibility of not just slowing down the processes of aging, but actually beginning to reverse them.
In 2019, a team including academics from Stanford University and the University of California, Los Angeles (UCLA), reported that their FDA-approved human clinical trial had wound back participants’ biological age by about two years.1 Crucially, improvement in the participants’ health scores suggested the treatment had extended their ‘healthspan,’ the number of years they could expect to remain fit and healthy into old age.
The study adds to the growing dataset from animal studies showing that aging and the onset of age-related disease is not fixed, but can be manipulated with medicines. Aging reversal has shifted from science fiction to science fact.
A long and healthy life
The modern science of aging reversal is not being pursued to try to make us live for longer. The primary goal is to make us live well for longer.2
Although conventional modern medicine continues to push out life expectancy, the years of good health we can expect has plateaued. Above the age of about 60, the odds of getting a host of age-related chronic diseases, from Alzheimer’s to cancer to arthritis, rises swiftly. Our extra years are lived in the grip of frailty, increasing ill health and incapacity.
The recent push in aging research has been to identify the underlying biological changes that leave us so susceptible to this wide range of chronic diseases as we age, with its high cost to individuals, to families, and to society.
Over the past five years, animal studies have identified some of the underlying aging mechanisms at play.3 A growing number of these animal tests seem to show that medical interventions that bring these mechanisms back into a fully functioning youthful state have whole-body benefits for the animal, extending their healthspan.
One of the greatest discoveries has been the major role played by the immune system, which seems to fall out of balance with age. The aged immune system becomes permanently activated, generating chronic low-level inflammation that causes collateral damage to healthy tissue around the body. At the same time, it becomes increasingly ineffective at fighting off infection, at responding to vaccines, and at keeping cancer at bay.
New links between aging and the immune system continue to be found. One of the most investigated areas of aging involves cell signalling pathways of a molecule called mTOR. Inhibiting mTOR signalling has improved health and extended lifespan in every species studied until this point – and in mice, one of its effects is to rejuvenate immune function. Now, that finding has been replicated in people. In 2018, pharmaceutical researchers reported that in a clinical trial of 264 elderly patients, mTOR inhibition therapy significantly reduced the number of infections participants contracted over the 12-month treatment period.4 Given that infection is the 8th-leading cause of death among over-65s, that result is significant in itself. The immune system’s wide-ranging role in whole-body wellbeing suggests the therapy would have multiple benefits in elderly people.
And a further connection between aging and immune function can be found in the lucky few individuals who somehow naturally enjoy such a long and healthy lifespan that they get to celebrate their 100th birthday. Intriguingly, centenarians appear to be enjoy maintained immune function right through to the final chapter of life.5 Could finding a way to maintain immune function in all the rest of us be the trick to maximising the healthspan?
Epigenetic aging
Rejuvenating the immune system, as a way to rejuvenate the whole body, was the tack taken by the California anti-aging team. They focused on the thymus, a small gland in the chest whose main role is to make essential immune cells called T cells.
Age-related decline in thymic function has been linked with multiple forms of ill-health. As long ago as 1986, researchers showed that using growth hormone to regenerate the thymus in rats rejuvenated their immune system.6 So the Californian team tested the idea of using human growth factor as part of a combination therapy to promote thymus regeneration in older people, in a group of nine healthy men aged between 51 and 65.
Perhaps the most innovative part of the California age reversal trial was the way that they measured the results. As well as using medical images to measure changes in the thymus, and analysing immune cell population subsets, the team used a new measure of overall biological aging called “epigenetic clocks”.
Epigenetics refers to the dynamic set of molecular annotations that decorate the DNA in our cells like Post-It Notes, and which dictate how our genetic blueprint is read and DNA transcription is modulated. By studying the way epigenetic marker patterns change through life – especially in our final years – UCLA researcher Steve Horvath has helped to pioneer the discovery of epigenetic patterns as a measure of biological age – a measurable epigenetic ‘clock’ in our cells.7 Analysing the epigenetic marker patterns on DNA taken from a patient’s blood sample can now use the epigenetic clock to objectively establish that individual’s biological age and probable lifespan more accurately than the number of birthdays they have seen.
The discovery of epigenetic clocks means researchers can measure the impact of potential anti-aging therapies in just a few months, rather than having to wait up to a decade or more to assess whether the intervention has delayed age-related disease onset.
Using epigenetic clocks, the California team showed that rejuvenating the immune system reversed the biological age of all the participants in the clinical trial. Even though the healthy individuals taking part already had an epigenetic age lower than their chronological age at the start of the trial, the treatment wound back their biological clock even further. On average, the epigenetic clock was reversed by 1.5 years by the end of the trial. Factoring in the 12 months that elapsed during the trial, the participants ended up 2.5 years better off than they would have been. Six months after treatment ended, the effects had persisted. The team is now planning a follow-up trial to test the therapy in a broader range of ages, ethnicities, and to include women.8
Exosomes and aging
As the authors of the California study note, using a broad-acting substance such as human growth factor as a drug has potential for side effects. But there are other ways to stimulate thymus regeneration. One of the most promising is to use exosomes.
Exosomes are nanoscale packets of biomolecules released by virtually every cell type in the body, and play a key role in cell to cell communication. One of the tasks they appear to perform is to deliver a key signalling molecule, called Wnt4, to the thymus. Falling Wnt4 levels – which happens as we age – contributes to thymus degeneration.
A research team in Europe recently engineered cells to produce exosomes enriched in Wnt4 and a related microRNA, miR27b.9 In mice, these exosomes can counteract thymus degeneration, a 2019 study showed. These engineered exosomes are a promising strategy for rejuvenating the human immune system to counteract age-related disease, the researchers concluded.
And that’s just one strand of research. A wide range of studies have shown how exosomes can play a key role in modulating and maintaining immune system function, and how exosomes from regenerative cell types such as stem cells could have a rejuvenating effect.10,11
In the quest for anti-aging treatments to stave off age-related diseases and extend healthspan, regenerating the immune system is just one of the promising avenues being explored.3 From reversing the dysregulation of energy production processes within cells, to clearing the slow accumulation of zombie-like ‘senescent’ cells that are major drivers of inflammation, there is a growing optimism that effective anti-aging therapies will soon be found. In each case, exosomes are among the front-running therapeutic options.12,13 Age reversal has entered the realm of science fact.
References:
1. Fahy, G. M., et al. Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell (2019), https://doi.org/10.1111/acel.13028
2. Bellantuono, I. Find drugs that delay many diseases of old age. Nature 554, 293 (2018)https://doi.org/10.1038/d41586-018-01668-0
3. Campisi, J. et al. From discoveries in ageing research to therapeutics for healthy ageing. Nature 571, 183 (2019) https://doi.org/10.1038/s41586-019-1365-2
4. Mannick, J. B., et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Science Translational Medicine 10, eaaq1564 (2018) https://doi.org/10.1126/scitranslmed.aaq1564
5. Strindhall, J., et al. No immune risk profile among individuals who reach 100 years of age: Findings from the Swedish NONA immune longitudinal study. Experimental Gerontology 42, 753 (2007). https://doi.org/10.1016/j.exger.2007.05.001
6. Kelley, K. W., et al. GH3 pituitary adenoma cells can reverse thymic aging in rats. Proceedings of the National Academy of Science 83, 5663 (1986). https://doi.org/10.1073/pnas.83.15.5663
7. Horvath, S., Raj, K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nature Reviews Genetics 19, 371 (2018) https://doi.org/10.1038/s41576-018-0004-3
8. Abbott, A. First hint that body’s ‘biological age’ can be reversed. Nature 573, 173 (2019)
9. Banfai, K. et al. Transgenic Exosomes for Thymus Regeneration. Frontiers in Immunology 10, 862 (2019) https://doi.org/10.3389/fimmu.2019.00862
10. Eitan, E., et al. Age-Related Changes in Plasma Extracellular Veiscle Characteristics and Internalization by Leukocytes. Scientific Reports 7, 1342 (2017) https://doi.org/10.1038/s41598-017-01386-z
11. Zhang, Y., et al. Hypothalamic stem cells control ageing speed partly through exosomal miRNAs. Nature 548, 52 (2017). https://doi.org/10.1038/nature23282
12. Wiklander, O. B. P., et al. Science Translational Medicine 11, eaav8521 (2019) https://doi.org.10.1126/scitranslmed.aav8521
13. Lui, S., et al. Highly Purified Human Extracellular Vesicles Produced by Stem Cells Alleviate Aging Cellular Phenotypes of Senescent Human Cells. Stem Cells (2019) https://doi.org/10.1002/stem.2996
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