Exosomes are one of the most promising potential treatments for staving off age- related disease, keeping us fit and healthy throughout our natural lives.

Modern medicine has been phenomenally successful at extending human lifespan, particularly for individuals born in the developed world. A baby born in the US today has a life expectancy of almost 79 years. In Australia it is 82 years, a full decade longer than a baby born in 1975. And this upward trend in life expectancy shows no sign of slowing. But while we are living for more years, the extra years we are getting are not necessarily good ones. The number of years we can expect to remain fit and healthy has not extended at the same rate as overall lifespan. We’re left with a situation where people can experience a prolonged period of declining health and increasing frailty in the last years of their life.

Our lifespan has extended, but our ‘healthspan’ remains little changed.

Tackling the healthspan problem will require a paradigm shift in the way we think about health and aging. “To delay the process, we need to keep people healthy, not just treat people with disease,” Eileen Crimmins from the Davis School of Gerontology at the University of Southern California recently wrote [1].

Researchers in the field of aging are seeking ways to extend our healthspan. And there is good reason to think this should be possible.

Today, the typical pattern of aging is that, for a person who lives for 85 years, they will experience 55 healthy years followed by 30 years of increasing ill heath and infirmity, Stanford University neurologist Tony Wyss-Coray recently told a webinar on aging [2]. During the period of decline, cardiovascular disease, diabetes, arthritis and neurodegenerative disease can all begin to take their toll.

And yet there are rare individuals who buck this trend, Wyss-Coray points out. These are the centenarians, who typically enjoy 90 years of good health and only begin to experience age-related disease in the last 10 years of life. These individuals not only show that humans are physiologically capable of long healthy life – they offer a model we can study in search for clues. Getting everyone to their 100th birthday is not the aim – dying at 85 after only 10 years of ill-health, rather than the current 30 years, would have huge benefits, for the individual but also for society at large, which is currently saddled with an escalating annual healthcare bill.

Wyss-Coray and his colleagues in the field are hunting down the biomolecules that seemed to associate with age-related illness, and those linked with good health long into life. They are looking for ways to tamp down the former while turning up the latter.

“We now know that a number of health outcomes linked to age—mortality, heart disease, functioning loss, cognitive loss—have very similar risk factors,” Crimmins writes. “They are all rooted in the physiological changes related to aging.” To extend the healthspan, we need to delay those changes as long as possible to keep the body in a physiologically youthful state.

“Treating” ageing – the classic drug molecule way
One option for extending healthspan might be targeted treatments in the form of small molecule drugs. This year, Daniel Kalmat at the Emory University Medical School in Georgia, US, published work that suggested some candidate compounds [3].

One of the most striking health discoveries of recent years has been the realisation that the bacteria in the gut play an intimate role in human health. Certain species are associated with good health: they help release nutrients in the food we eat, enhance immune system function, help maintain the cells that form the lining of the gut, and help fight off bacteria that cause disease. Some studies hint their beneficial effects even extend to healthy brain function [4].

Noting that aging is associated with changes in the population of gut microbes [5], Kalmat and his team looked at the compounds secreted by the beneficial gut micobes that tend to be lost with age. They identified a family of molecules called indoles. When these compounds were tested in animal, they extended the healthspan of a range of organisms, including worms, flies and mice. The compounds induced patterns of gene expression in old animals similar to those of youth. When an effect like this is seen across a range of animal species, it increases the chance it could carry over to humans, too. “These data raise the possibility of developing therapeutics based on microbiota-derived indole or its derivatives to extend healthspan and reduce frailty in humans,” Kalmat and his team concluded.
And there are plenty of other age-related targets to aim for with small molecule drug. Another well-established change in older individuals, for example, is the increasing dysfunction of their mitochondria, the energy-generating machinery of the cell.
In another promising discovery, a team from the National Institute on Aging at the US National Institutes of Health showed a molecule called tomatidine, derived from tomatoes, slowed mitochondrial decline in animals. The treated animals got a small boost in lifespan, but a big boost in healthspan, remaining healthy far longer into life than the untreated animals did.

“Treating” ageing – the Regenerative Medicine way
Underlying many of the physiological changes the human body undergoes with age are concomitant changes in patterns of signally between cells as the body transitions from a resilient regenerative state into one of stress and disrepair.

As well as metabolic changes, significant changes occur within immune system signalling, for example – with far-reaching effects. The body descends into a state of chronic low-grade inflammation – a condition dubbed ‘inflamm-aging’ – which contributes to the onset of age-related conditions including type II diabetes, Alzheimer’s disease, cardiovascular disease, frailty, osteoporosis and cancer [6].

Exosomes, nanoscopic packages of signaling molecules released by virtually every tissue in the body, are essential mediators of cell to cell signaling – including communication between immune cells. So it is no surprise that exosomes are being found to play a role in age-related disease.
This year, one of the first studies on the subject confirmed that the number of exosome circulating in the blood decline with age (see Turning back the body clock). Their interactions with recipient cells also changed [7]. Monitoring exosome levels in aging individuals could become an invaluable diagnostic tool, indirectly expanding the healthspan by revealing the presence of underlying health conditions that can then be treated early before any damage is done.
But exosomes also offer opportunities for direct treatment, too. Individuals who currently enjoy a long healthspan typically get plenty of exercise and keep to a healthy weight. Endurance exercise in particular seems to stave off the changes in metabolism that precede obesity and the onset of type-II diabetes.

Last year, Mark Tarnopolsky from McMaster University in Canada and his colleagues showed that exosomes released by the muscles and other organs during exercise probably play a key role in the system-wide benefits of endurance workouts (see Clearing the hurdles with exosomes) [8]. The discovery raises the possibility that exercise-derived exosomes produced in the lab could offer a new way to treat obesity and its related diseases.

Perhaps the most promising set of exosomes for expanding the healthspan are those derived from stem cells.
When we are young, we recover from injury quickly. That’s in part down to the higher number of circulating regenerative stem cells we have in our bodies in our youth. This natural decline in stem cell numbers with age triggered the idea that by topping up our levels of stem cells, we could enhance the body’s capacity for self –repair well into old age. It is now widely recognised that the benefits of stem cell therapies derive from the regenerative exosomes the stem cells release, which stimulate repair in damaged cells. Exosomes themselves are now regarded as the most promising option for developing a therapy to extend the body’s natural regenerative mechanisms (see Exosomes versus stem cells) [9].

Chronic ill health in old age is a system-wide problem. Stem cell exosomes could offer the system-wide solution that closes the gap between lifespan and healthspan.

References
[1] Crimmins, E. M. Lifespan and Healthspan: Past, Present, and Promise. Gerontologist 55, 901-11 (2015).
[2] http://www.alzforum.org/webinars/webinar-cortex-aging-too-fast-blame-tmem106b-and-progranulin
[3] Sonowal, R. Indoles from commensal bacteria extend healthspan. Proceedings of the National Academy of Sciences of the USA 114, E7506 (2017)
[4] Leung, K. and Thuret. S. Gut Microbiota: A Modulator of Brain Plasticity and Cognitive Function in Ageing. Healthcare (Basel) 3, 898–916 (2015)
[5] O’Toole, P. W., Jeffery, I. B. Gut microbiota and aging. Science 350, 1214-1215 (2015).
[6] Fougère, B., Boulanger, E., Nourhashémi, F., Guyonnet, S., Cesari, M. Chronic Inflammation: Accelerator of Biological Aging. The Journals of Gerontology: Series A 72, 1218–1225 (2017).
[7] Eitan, E. et al. Age-Related Changes in Plasma Extracellular Veiscle Characteristics and Internalization by Leukocytes. Scientific Reports 7, 1342 (2017)
[8] Safdar, A., Saleem, A. & Tarnopolsky, M. A. The potential of endurance exercise-derived exosomes to treat metabolic diseases. Nature Reviews Endocrinology 12, 504–517 (2016).
[9] Phinney, D. G. ,and Pittenger, M. F. Concise Review: MSC-Derived Exosomes for Cell-Free Therapy. Stem Cells 35, 851-858 (2017).