Understanding regenerative medicine’s point-of-difference
Companies testing exosome-based therapies are developing completely new ways to tackle the wide array of medical conditions that afflict us in old age.
Exosomes from stem cells are an emerging regenerative medicine that could disrupt the way age-related degeneration is treated, including problems such as cardiovascular disease, neurodegeneration, osteoporosis and erectile dysfunction.
But what is regenerative medicine and how is it different from other drugs?
Understanding regenerative medicine’s point-of-difference
Regenerative medicine is different from typical drugs – and potentially much more powerful.
Many drugs treat the symptoms of a problem, not the underlying cause. As an example, insulin injections reduce blood sugar levels in people with type 1 diabetes (T1D). Without insulin injections, the levels of sugar rise to dangerous levels within hours, because the person has insufficient insulin-producing beta cells in their body. So, T1D patients are on insulin injections for life.
Regenerative medicine would treat T1D differently. In a regenerative medicine approach to T1D the strategy is to do two things at the same time. Firstly, replenish the beta-cell population in the patient’s body to start producing insulin naturally, and secondly to suppress the patient’s own immune system from attacking beta cells, which is the underlying cause of the disease.
Success would mean the treated person was free from glucose monitoring and injections through the day because their own beta cells were back on the job.
Similar scenarios apply in other conditions associated with aging. Here are three examples.
After a heart attack, many heart muscle cells die and the heart loses the ability to pump blood, so the patient’s health is compromised or the patient dies. But in pre-term babies, damaged heart muscle cells can be replenished from their own stem cells. What if we could turn that regenerative capability back on in adults, so that damaged heart cells could be replaced by healthy new ones?
As we age, we can suffer a loss of cells in critical regions of the brain. In Parkinson’s disease, the affected region is the substantia nigra. In Alzheimer’s, it’s the loss of neurons and connections in the cerebral cortex and some subcortical regions. The latest science suggests that adult brain cells can, in certain circumstances, be replaced. What if we could switch that regenerative program back on to treat Parkinson’s or Alzheimer’s disease?
In osteoporosis – a problem affecting bone density and bone strength – there is an imbalance between bone formation and bone resorption, leading to the loss of bone density. Bone formation is a balance between osteoclasts (cells that remove bone material) and osteoblasts (cells that add bone tissue). In youth, the osteoblasts are more active than the osteoclasts so bones grow. As we age the osteoclasts become more active and the osteoblasts are less active, so bone formation reverses and bone density decreases. To treat the condition, regenerative medicine would seek to revert the balance between osteoclasts and osteoblasts back to equilibrium, bringing bone density back to healthy levels.
Erectile dysfunction after pelvic surgery, such as for prostate or colorectal cancer, appears to be caused by increased cell death (apoptosis) of corpus cavernosum smooth muscle cells (CCSMCs). This damage has been seen as always irreversible.1 Regenerative medicine would seek to reverse erectile dysfunction by replenishing the population of CCSMCs.
So regenerative medicine seeks to harness the body’s own regenerative capacity to heal the underlying causes of medical and other problems.
Aging badly is not inevitable
Many people incorrectly assume that frailty and disease are simply an inevitable part of getting older. In fact, the first evidence that this is not the case came in 1939, when researchers first noticed that mice and rats given a calorie-restricted diet lived for longer. The observation that calorie restriction extends lifespan and ‘healthspan’ – the number of years spent fit, active and disease-free – has since been repeated in many organisms, from yeasts and worms to primates.2
We now know that the effects of aging can be reversed in cells and also in animals. Evidence increasingly suggests that regenerative medicine is a feasible aim.
Recent publications in leading scientific journals describe studies showing the reversing of age-related impairment. In August 2019, for example, a Nature paper demonstrated new ways to reverse older stem cells to a younger, healthier state – reversing brain stiffness and brain stem cell dysfunction.3 In July 2018, scientists demonstrated reversal of age-associated skin wrinkles and hair loss in a mouse model.4 In the May 13th 2019 edition of Nature Medicine, a paper demonstrated that the cognitive deficits in the brains of aged mice can be reversed.5 And in March 2019, research published in the EMBO Journal showed that in mice, clearance of senescent cells – damaged cells that have stopped dividing and are a major inflammatory trigger – reverses heart failure in older animals.
There are many other recent publications pointing to the same conclusion, aging effects can be reversed in animals. But can we reverse aspects of aging in humans?
One fascinating 2017 research publication hints at the possibilities. The paper reported that fourteen patients (13 men and 1 woman, with a mean age of 65 years) receiving anticancer therapy saw an unexpected side effect of hair repigmentation, a return of hair colour.6
The first clinical trials testing the idea regenerative medicine could reverse aging effects in people are now underway. Clinical trial NCT02432287 is seeking to determine whether the anti-aging effect seen in animals given metformin, a drug already approved for type 2 diabetes, translates to humans. And in 2018, the first human clinical trial of a drug that clears senescent cells began.
Shared underlying biological causes of degeneration and decline
These clinical trials could be the first step toward the fundamental rethink of the way we approach age-related diseases that leading researchers are calling for.7
Simply continuing to treat each age-related disease as a ‘silo’ does not solve the health span problem. Cancer is the leading cause of death in Australians over 65. But even if, by some miraculous breakthrough, a researcher discovered a cure for all cancer – this would only cause a modest bump in life expectancy and healthspan, statistical analysis has shown. Cure cancer and the many other age-related chronic diseases – stroke, heart disease, dementia, osteoarthritis, diabetes – would take its place.
A growing body of research has identified a handful of underlying biochemical ‘aging pathways’ that tend to go awry as we age, leaving the body so much more susceptible to a diverse range of chronic diseases.8
These aging pathways include mitochondrial function, DNA damage, protein synthesis, nutrient sensing, oxidative chemistry and damage, inflammation, senescence and cell processes (e.g. autophagy).9 Regenerative medicines can be used to target combinations of the age-related pathways. Rather than trying to treat each age-related disease individually, regenerative medicines such as exosomes offer the possibility of treating the underlying causes that make us susceptible to the whole host of illnesses that afflict us with age.
Researchers from Yale University in 2018 showed that combinations of drugs targeting distinct subsets of the aging pathways can cause synergistic lifespan benefits in worms.10
One of the most striking observations in age-related research was that older mice given blood of young mice saw a dramatic improvement in health and vitality.11,12 Several components of the blood have been implicated in the regenerative effect. Exosomes are produced from platelets within the blood and could be the mechanism of action which has enabled the improvement in health and vitality as shown in the above studies.
Exosomes to the fore
Exosomes – nanoscale packets of biomolecules including proteins and RNA, naturally released by various cells in the body, including stem cells – appear to be a very promising regenerative therapy, and the evidence of their potential is growing all the time.
The number of extracellular vesicles (EVs) (or exosomes) that naturally circulate in the human body declines significantly with age, researchers from the National Institute on Aging (NIA) in Maryland, US, recently showed.13 As well as a clear decline in levels of circulating exosomes with age they also noted significant differences in the way older individuals’ exosomes were taken up by immune cells, and the immune cells’ subsequent response.
This year, a Japanese research team drilled into the regenerative properties of circulating exosomes, and an enzyme called eNAMPT that the exosomes carry. This enzyme promotes the production of NAD+, a key component of cellular metabolism previously shown to decline with age, and earmarked as a potentially critical component underpinning age-related disease. In mice and humans alike, levels of eNAMPT in circulating exosomes decline with age.
But when the Japanese team dosed aged mice with extra eNAMPT-rich exosomes isolated from young mice, they boosted their health and fitness and extended their lifespan.14 It’s a promising avenue of research for using exosomes as a health span-extending therapy in humans, the researchers conclude. And just one of the ways exosomes isolated from regenerative sources, such as stem cells, look poised to contribute to the regenerative medicine revolution.
After a heart attack, exosomes can co-ordinate the increased circulation of progenitor cells, which can then increase the level of cardiac repair.15 Another study published in 2019 showed that myocardial infarction (MI), exosomes secreted by heart muscle stem cells provided cardioprotective effects, activated regenerative signals, and augment cardiac repair.16
In erectile dysfunction (ED), researchers reported in 2019 that exosomes purified from mesenchymal stem cells treat ED in rats by inhibiting apoptosis in corpus cavernosum smooth muscle cells.1 A further report from the same research group showed that exosomes from human stem cells successfully treated ED in a diabetic rat model.17
Exosomes are also seen as useful for treating multiple neurodegenerative diseases due to their anti-inflammatory, neurogenic and neurotrophic effects.18 In an acute injury, neural stem cell-derived exosomes reduce apoptosis (cell death) and neuroinflammation.19
In osteoporosis, exosomes have been shown to promote osteoblast proliferation.20 In 2019 researchers reported that exosomes could be utilised to treat several skeletal disorders such as osteoporosis and impaired fracture healing.21
Exosomes and the regeneration revolution
With regenerative medicines such as exosomes ably demonstrating their potential, a pivotal moment in healthcare has arrived. Treating the underlying causes of disease, by activating or reactivating the body’s natural repair mechanisms, would revolutionise the way medicine is practised. Exosomes are being shown to be useful to treat a variety of medical conditions and have the potential to address more than one of the common aging pathways at the same time.
Soon, a fit and healthy old age might be enjoyed by many more than just the lucky few.
- Ouyang et al. MSC-derived exosomes ameliorate erectile dysfunction by alleviation of corpus cavernosum smooth muscle apoptosis in a rat model of cavernous nerve injury. Stem Cell Research & Therapy 9, 246 (2018). https://doi.org/10.1186/s13287-018-1003-1
- Campisi, J. et al. From discoveries in ageing research to therapeutics for healthy ageing. Nature 571, 183 (2019)
- Segel, M., et al. Niche stiffness underlies the ageing of central nervous system progenitor cells, Nature (2019). https://doi.org/10.1038/s41586-019-1484-9
- Singh, B., et al. Reversing wrinkled skin and hair loss in mice by restoring mitochondrial function. Cell Death & Disease 9, 735 (2018). https://doi.org/10.1038/s41419-018-0765-9
- Yousef, H. et al. Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nature Medicine 25, 988 (2019). https://doi.org/10.1038/s41591-019-0440-4
- Rivera, N., et al. Hair Repigmentation During Immunotherapy Treatment With an Anti–Programmed Cell Death 1 and Anti–Programmed Cell Death Ligand 1 Agent for Lung Cancer. JAMA Dermatol. 153, 1162 (2017). https://doi.org/10.1001/jamadermatol.2017.2106.
- Bellantuono, I. Find drugs that delay many diseases of old age. Nature 554, 293 (2018)
- Mazucanti, C.H., et al. Longevity Pathways (mTOR, SIRT, Insulin/IGF-1) as Key Modulatory Targets on Aging and Neurodegeneration. Curr Top Med Chem. 15, 2116 (2015).
- Kim. S. K. Common aging pathways in worms, flies, mice and humans. Journal of Experimental Biology 210, 1607 (2007). https://doi.org/10.1242/jeb.004887
- Admasu, T. D., et al. Drug Synergy Slows Aging and Improves Healthspan through IGF and SREBP Lipid Signaling. Developmental Cell 47, 67 (2018). https://doi.org/10.1016/j.devcel.2018.09.001
- Katsimpardi, L. et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344, 630 (2014). https://doi.org/10.1126/science.1251141
- Castellano, J.M., et al. Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature 544, 488 (2017) https://doi.org/10.1038/nature22067
- Eiten, E. et al. Age-Related Changes in Plasma Extracellular Veiscle Characteristics and Internalization by Leukocytes. Scientific Reports 7, 1342 (2017)
- Yoshida, M. et al. Extracellular Vesicle-Contained eNAMPT Delays Aging and Extends Lifespan in Mice. Cell Metabolism (2019), DOI: 10.1016/j.cmet.2019.05.015
- Cheng, M. et al. Circulating myocardial microRNAs from infarcted hearts are carried in exosomes and mobilise bone marrow progenitor cells. Nature Communications 10, 959 (2019). https://doi.org/10.1038/s41467-019-08895-7
- Li, N. et al. New Insights into the Role of Exosomes in the Heart After Myocardial Infarction. J Cardiovasc Transl Res. 12, 18 (2019). https://doi.org/10.1007/s12265-018-9831-z
- Ouyang, B. et al. Extracellular Vesicles From Human Urine-Derived Stem Cells Ameliorate Erectile Dysfunction in a Diabetic Rat Model by Delivering Proangiogenic MicroRNA. Sex Med 7, 241e250 (2019). https://doi.org/10.1016/j.esxm.2019.02.001
- Vogel, A. et al. Neural stem cell derived extracellular vesicles: Attributes and prospects for treating neurodegenerative disorders. EBioMedicine. 38, 273 (2018). https://doi.org/10.1016/j.ebiom.2018.11.026
- Rong, Y. et al. Neural stem cell-derived small extracellular vesicles attenuate apoptosis and neuroinflammation after traumatic spinal cord injury by activating autophagy. Cell Death Dis. 10, 340 (2019). https://doi.org/10.1038/s41419-019-1571-8.
- Zhao, P. et al. Exosomes derived from bone marrow mesenchymal stem cells improve osteoporosis through promoting osteoblast proliferation via MAPK pathway. Eur Rev Med Pharmacol Sci. 22, 3962 (2018). https://doi.org/10.26355/eurrev_201806_15280
- Pethö, A. et al. Exosomes in Extracellular Matrix Bone Biology. Curr Osteoporos Rep. 16, 58 (2018). doi: 10.1007/s11914-018-0419-y