The International Society on Aging and Disease (ISOAD) recently held its third international conference in Nice, France, bringing together researchers – and longevity activists – from around the world. Journalist and supporter of anti-aging research Oliver Rowland attended the event and has made this great report packed with information gathered from interviews and talks at the event.
Professor Eric Gilson
After working in Lyon, Prof. Gilson founded the Ircan Institute for Research on Cancer and Aging in Nice in 2012. “It was perhaps the first institute that specifically aimed to couple the themes of aging and cancer in the same laboratory, even if the links between them had been known to some extent,” he said. “That was its originality.”
We’ve laid the foundations – to have the expertise, the right people, the right models – and I think we’re going to have important answers for the role of telomeres in aging and, more generally, cellular senescence, which is the favorite current target of a lot of pharmaceutical or fundamental research that we are revisiting via our original models. We will, I think, have some important results.
He said that they are researching mice, human cells, yeast, and marine animals (cnidaria).
We will also have results in the area of regeneration. The clocks of aging, through cellular senescence and the processes of regeneration – what is it that means that corals and sea anemones, even certain fish like zebrafish, regenerate much more than humans do; what are the mechanisms? It’s linked to aging, because aging is associated with greater difficulty in regenerating our tissues. I think we’re going to contribute in very important ways.
Prof. Gilson said that the goal is not necessarily about finding a specific treatment but to discover the common biological processes behind all pathologies so as to intervene before they develop.
It’s the new concept in medicine, to intervene simultaneously on a whole range of pathologies that were not previously seen as linked: diabetes, neurodegenerative diseases, cancers, which are all dealt with by different specialist doctors but which all have mechanisms in common.
There are even certain drugs [that can target more than one pathology] like metformin, which is now being trialed against cancer as well [as diabetes]. There is going to be more and more crosstalk. That’s why, at Ircan, we have people working on different areas, immunology, metabolism, senescence, to create synergy. That’s what characterizes what I call the new biology.
One of the benefits of conferences like this is to bring together people who don’t normally meet. It’s different from ones where you just focus on one topic, whether it’s telomeres or autophagy, neurodegenerative disease, and everyone knows each other. Multidisciplinary meetings are very important, and there are not that many of them, including both clinicians and pure scientists such as mathematicians. It’s very important to do that.
We’re not there yet, but it’s the route – integrations in terms of biological processes or of mathematical models or big data. Biology of aging is a very wide-ranging biology. There are famous journals which are starting to define common characteristics, and these are important stages in our way of thinking, but I’m not sure yet if we are aware of everything and I think there’s still some way to go.
I think that we are going to have more and more preventative methods so as to diminish the incidence of illness linked to age in the general population. I really believe that. There are a lot of trials under way, for example with rapamycin. A big question is whether we should do preventative action on the whole population or do it in a more targeted way. Should we pre-treat healthy people? We are starting to have certain molecules now. It’s why this area of medicine is so interesting.
He said that much of his own work relates to telomeres, which are interesting as one of the clocks of aging.
We are programmed to age at a certain speed, and telomeres don’t do everything, but they are part of the clock. It’s not to say there aren’t others that they interact with, or that they can’t be modulated by the environment. So they’re not an absolute clock, but a relative one, but a clock all the same.
Dr. Holly M. Brown Borg
Dr. Brown Borg, a biologist and biogerontologist from the University of North Dakota, said that she has been looking at effects of a methionine-restricted diet. Methionine is an amino acid that she said is especially found in red meats. It is also in many other foods in varying amounts, with high levels in poultry, fish and Brazil nuts, and fairly high in dairy products; therefore, a vegetarian, particularly a vegan, diet generally gives the lowest amount.
She said that if you have a diet with 80% reduction in methionine to mice, it extends lifespan; in mice bred for accelerated aging, it gave 50% extra life. They lived for 18 months instead of 12 months.
She added that growth hormone appears to be involved in how the body senses different nutrients in the diet and that animals without it do not respond to the reduced methionine diet. Regarding growth hormone, she said that we, as humans, have most of this in our teens until age 25, at which point it declines but doesn’t get really low until past age 70.
It stimulates [cell] proliferation, so this [reduction] reduces your potential for cancer as you age. On the internet, you will see a lot of people advising taking growth hormone, but it will increase cancer rates and has a suppressive effect on numerous enzymes in the metabolic world. Though it does increase muscle mass and reduces adiposity, it has no effect on function or strength so it’s only aesthetic. Athletes abuse it because it increases muscle mass if you are taking a lot of protein, but the literature on nutrition and aging shows high levels of protein are not good either, as it promotes cancer. There’s a lot of research that suggests that low growth hormone levels promote longevity, so it’s not something you want to boost.
Dr. Brown Borg added that, in the short term, a high-protein diet may sometimes help with weight loss but that, in the long term, it is “not good at all”, much like the ketogenic diet, which is probably also only good for “short spurts” and not for long-term health.
Asked about the benefits of a low-carbohydrate diet, she said that it is probably better to eat moderately high amounts of carbohydrate and fat while keeping protein low for long-term health. “High carb or high fat are not bad, per se, if those two are balanced; I mean, they shouldn’t be too high; but it’s high protein which should be avoided long-term.”
Dr. Oliver Bischof
Dr. Bischof is a biologist from the Institut Pasteur in Paris, but he stressed that his views were his own and not his institution’s, and he added that Clémentine Schilte is leading the group on aging at Pasteur. He noted that the institute has not increased this focus since last year’s conference on cellular senescence, which Dr. Bischof organized, and, in fact, there has been a recent change in leadership at the institute and it is too early to say whether or not aging will be prioritized.
Asked if the Institut Pasteur Lille (which is independent of the main institute in Paris) still has a strong aging focus (it has run two conferences on ‘healthy aging’ and created a research center on the subject), he said that its director general, Patrick Berche, who was the driving force, is leaving, and so Lille’s future focus on aging is uncertain.
In general, everyone is aware of the problem [of aging], but things are a bit static. There’s no one really saying ‘Okay, let’s do it.’ I don’t know how this can be better organized; it’s a problem. In the US, they are now releasing huge budgets to do that. Europe usually waits, and waits, and waits but doesn’t act.”
In his talk at the conference, Dr. Bischof said that we “have to find a way to reset the aging clock” as he showed slides of Barack Obama before and after his presidency and said that the aim would be to take him back to the way he looked before.
As he explained, we now know that senescent cells build up as we age, in different organs and tissues, and that they are directly linked to frailty, illness, and death, and mouse research shows that eliminating senescent cells from the body shows that we can rejuvenate an older mouse to a younger-looking mouse. He also discussed genome-wide studies. “Can we reprogram senescence and go back in time? Yes, we can.” So far, his own research has been on cell cultures.
This is reverse genetics; you knock down a component. In our case, it was a transcription factor. You reduce the function of that component, and you see that reversion.
It’s just at the beginning, the first proof of concept that with this type of analysis that we’re doing, this multidimensional profiling, integration of different omics, genome-wide datasets, that we can elucidate mechanisms and find new factors that may eventually be targets to be exploited in order to go further and see how they work in healthspan extension in model systems like the mouse.
He said that he is in favor of start-up companies setting up to try anti-aging approaches:
This culture of start-ups is growing now in France, and I think it’s a good thing to try to lift the fundamental findings in aging biology to the next level and see how we can apply them. There is now so much happening in the field of [cellular] senescence, so many companies, mostly in the US, trying to exploit it. There’s a real momentum, and if anything comes out as really positive – we finally get the positive control for senescence elimination, a positive impact on the treatment of age-related diseases – then, hopefully, that will launch an avalanche of financial interest. In the end, it’s money that makes the difference. I think then we can diversify and instigate new start-ups. Biotech companies are usually very reserved in financing the beginnings of a potential druggable target and drug, and usually wait till something precipitates, and then they exploit you and buy you and that’s the end of that.
We tried it with a consortium, but it was difficult. We had interest, but nothing materialized. They usually want something very specific and already almost completely worked out. That’s why the other route of making a start-up as soon as you think you have something you think is exploitable; this needs to be facilitated. You need organizations and funding strategies to facilitate this transition from fundamental findings to early clinical applied science. This is where we still have to improve.
He said that funding strategies can be diversified:
Public money is always important, mostly for fundamental research, and the private sector has to realize that some of that funding can go into high risk but also high gain, and you diversify your assets to minimize risks. Crowdfunding is also a good thing to do. There have to be different mechanisms to find ways to funnel money into this kind of research and accelerate it. Without money, you don’t go far. We need creative people working together with scientists to find ways to finance. Public money can’t do it by itself. Concerted action with different stakeholders working together to push it is what is needed. We need to learn how to access money or convince people to get it.
Dr. Bischof said that what is ideally needed is, for example, a substance that can be injected into someone’s knee to make osteoarthritis disappear – that way, things would really start to move in terms of funding.
One questioner after his talk said that senescence happens even in utero and is not always harmful, and Dr. Bischof agreed that there was ‘good’ and ‘bad’ senescence and said that his team’s wide-ranging research on different kinds of cells would help clarify this.
Dr. Guido Kroemer
Dr. Guido Kroemer from the University of Paris Descartes was the first main speaker of the weekend, and he discussed the topic of calorie restriction mimetics as so-called anti-aging elixirs. One of the event organizers, Ilia Stambler of the Israeli Longevity Alliance called it a “really important development”. According to Dr Stambler:
You don’t make people starve, you mimic the biological processes involved, and you can sell it as a drug. At the moment, it’s mostly been at the stage of mouse tests, and of course with mice, everything works perfectly, but they have several treatments that can readily be applied to humans, such as spermidine and resveratrol analogues.
Spermidine induces autophagy, which fosters the renovation of tissues. It can be found in certain foods like mushrooms, broccoli and nuts. Dr. Kroemer also found that it changes the metabolism.
Anti-aging activist Didier Coeurnelle of Heales, who helped with organizing this event, said that the update on calorie mimetics was interesting, though they appear more likely to help increase average lifespan than to increase maximum lifespan. He also explained that they are also more useful for people in somewhat poor health and fitness as opposed to people who already do as much as possible to be healthy. He found it frustrating that even with good genes and lifestyle, people still die around 90 years old, and we haven’t found the solution yet.
Ilia Stambler said early in the conference that there were several talks showing the feasibility of stem cell therapies against major age-related diseases such as stroke and Alzheimer’s. “There’s a lot of developments in this area in China, with a lot of research approved for human clinical trials and it looks promising. Probably some other places should learn how to fast-forward this.”
Dr. Robert Chunhua Zhao
Activist and scientist Edouard Debonneuil of the International Longevity Alliance said that he found a presentation by Chinese scientist Robert Chunhua Zhao especially impressive, as his research on mesenchymal stem cells is entering clinical trials. Dr. Debonneuil explained it thus:
There is debate as to whether they are really stem cells, but he showed that yes, they are, and he showed, which is already established, that they can be introduced without much danger because it modulates the immune system so that it’s well accepted, and it does help a lot of diseases, including cardio-vascular issues, such as cardiac insufficiency. They are doing phase two clinical trials, which is surprisingly advanced. It’s very tissue-specific or disease-specific. They inject them at local sites.
He said that this came along with the news that in the United States, the FDA had been blocking research on IPS-produced stem cells.
The trouble is that it can create teratomas – cancers – so researchers did not find them in their tests, but there is always a risk, whereas with MSCs, which are a natural component of the body, they are easy to use because of the local attenuation of the immune response.
Dr. Guo-Yuam Yang
On the third day, Dr. Guo-Yuam Yang of Shanghai Jiao Tong University also talked about research into stem cell therapy to help people recover from stroke, saying that they could take stem cells – MSCs, ESCs, NSCs, iPSCs – from various kinds of tissues, including the hippocampus, and replacement with them can “induce immune response, neuroprotection, angiogenesis, neurogenesis and oligodendrogenesis, helping with tissue repair”.
He said that endogenous stem cells alone may not be enough, so they can also take exogenous stem cells from embryonic tissue and bone marrow and inject it into the injured brain area. He further explained that clinical trials on these cells in phases 1, 2, and 3 are showing some good results and that they had also found that OPC [a kind of nerve cell] transplantation reduces ischemic stroke injuries, leading to improved results in memory tests, and that they were also getting “very good results” for spinal cord injury repair.
Dr. Francesca Cirulli
Dr. Francesca Cirulli from the Instituto Superiore di Sanita in Rome looked at aging biomarkers in animal models in her talk, especially the effects of oxidative stress. She defined aging as “the aggregate of all processes that can reduce the well-being of an individual” and said biomarkers can be defined as factors which predict future healthspan better than simple chronological age. She explained that we should think of aging as a process that starts in the mother’s womb and may eventually lead to disease.
She said that the brain is especially susceptible to oxidative stress, partly because of lower than usual levels of enzymes that can detoxify it. She has been collaborating with researchers in Milan, who have shown how knocking out the p66(Shc) gene in animals helps protect against cancer, makes them leaner and more resistant to oxidative stress, and giving them a healthy appearance in older age compared to other mice. It also produced 30% longer lifespans.
She also discussed another study, which showed how mice with the gene knocked out were more resistant to metabolic stress due to their mothers having been obese because of a high-fat diet (one aging factor that starts in the womb). The researchers were also able to replicate the benefits of having the gene knocked out by giving a certain compound to the mothers, which reduced the level of oxidative stress in the womb.
Ilia Stambler chaired a panel on public support for aging and age-related diseases, including talks by Thierry Galli of Inserm’s Center of Psychiatry and Neurosciences in Paris, Didier Coeurnelle from the Heales association in Brussels, and Anton Kulaga of the Computational Biology of Aging group at Romanian Academy in Bucharest.
Prof. Galli, who coordinates aging research at Inserm, the French national institute of health and aging research, said that they had realized several years ago that they needed to prioritize aging research. He said that Inserm’s CEO had allowed teams to work together on aging-related topics.
AgeMed, the Inserm program on aging, and a program on microbiota were the first two programs. Earlier this year, another program was launched on genomic variations, and another program called Human Development Cell Atlas is starting. This is a cell atlas of the human embryo/fetus, which, he said, was not well-known at all. “There is a very strong school in France of embryology, so I thought it was important we strengthen this domain – with aging and the starting of life in the embryo, we have brought together the A and the Z,” he said.
These Inserm programs that bringing together different teams are known as “programmes transversaux”, or cross-cutting programs, he said.
On aging research, he advocated the studying of aging of cells and tissues as the starting point. As Prof. Galli explained:
We need to know the basic principles of what aging is. Under the supervision of myself and of Etienne Hirsch, in charge of neuroscience at Inserm, the goal is to bring together French leaders in the field to tackle some of the most pertinent medical and scientific challenges regarding the mechanisms of aging and find potentially innovative strategies to fight age-related disease and pathologies as a long-term end goal once we know some basic principles.
He said that 77 teams registered their interest, that a selection was made by a scientific advisory board of European experts, and that Eric Gilson was made overall coordinator. There are now 13 groups and an industrial partner – Dassault, which is not only involved in aviation but also software development, including for analysis of data in biology.
There will shortly be a new CEO at Inserm, and Prof. Galli said that one of his goals will be to convince them to continue this program.
Prof. Galli said that Guido Kroemer, who is not part of the program, “already has a whole panel of proposals to age better, and we hope from all of this that France and Inserm will be in a good position to make progress on aging.”
Inserm is also working with Quebec, which is launching a similar program, and hopes to make more international links.
He said that the organization would soon look to improve its communication with a website and a Twitter account.
Ilia Stambler said that the Israeli Longevity Alliance and the Seniority Association – the Senior Citizens Movement both advocate for biomedical research in aging to facilitate the development of therapies that intervene against the root cause of age-related disease, which is aging.
He said that not enough is spent on this field yet, and too few people are working on it – in the United States, $3 trillion a year is spent on health, but 99% of that is related to treating disease and only 1% or less is spent on prevention. Meanwhile, only about 3% of the EU’s Horizon 2020 budget goes towards aging-related issues, and the part for development of therapies and regenerative medicine is only about 0.5%. He mentioned that most of the money goes on technology to assist the elderly.
He said that the answer is to convince the general public and create political pressure. Activism can be on the personal level or the global level; for example, the WHO’s global strategy and action plan on ageing and health, which was adopted in 2016, has specific objectives to promote research and measurement of healthy aging and to test interventions. “We need to make people more aware of such clauses so they don’t just remain in papers that nobody reads.” The conference’s organizers, ISOAD, had drawn up national policy suggestions that had been translated into 12 languages and submitted to several governments. “We need to bother governments to say this is important.”
He said that advocacy for anti-aging is only about 10 years old but is beginning to show results. For example, WHO had nearly neglected to put the issue of healthy aging into its work plan, which extends to 2023.
There was an outcry by many organizations, including ISOAD; as a result, WHO included aging health into its program, with the target of reducing age-related disability. There was also success with parallel initiatives, such as the Biogerontology Research Foundation and the International Longevity Alliance’s effort to introduce a new modifier into the International Classification of Disease – ‘aging-related’ – which recognizes that aging is a major factor in disease.
He said that other ways to do advocacy included creative ideas to promote October as Longevity Month, such as through video collaborations with big YouTube channels, which were recently organized by LEAF.
Dr. Bischof raised the issue of whether aging itself must be classified as a disease so that researchers may more openly work at combating it. Eric Gilson said:
In public conferences, when you say you work on aging, and one goal is for elderly people to feel better, you have very good feedback, but when you say you work on disease so that people will live longer, you have very bad feedback, but both are linked. It’s an equilibrium, which, in the minds of the people, is difficult to understand. People say we will have a society with billions of old people. They don’t react positively to that. They react well that we will have less people with Alzheimer’s and more old people in good shape.
Edouard Debonneuil said that ‘XT9T’ was the new ICD11 code for ‘aging-related’ and explained:
A group spent a year on it for ILA and proposed 77 diseases that are in fact just processes of aging. It was refused but and they just accepted that it’s ‘aging-related’, but it means for example that on doctors’ computers, when they treat your disease they will have to fill in if it’s aging-related or not and it means discussions will take place with Pharma to know if they can have a drug approved, if it’s linked to some aging process. It’s a complex path to go for Pharma to be interested in the aging process.
Didier Coernelle talked about how to encourage support for clinical trials against aging, which should be carried out with the aim of rejuventating people who are already old. He advocated for a ‘Manhattan Project against senescence’, which could be at the global or European level.
Among other points, he said that one problem is that we currently lack clear enough language to describe aging in the sense of merely ‘advancing in [chronological] age only’ as opposed to ‘being in bad shape’.
It is very possible to find treatments against aging in 15-30 years, but it will be very complicated and expensive. Senescence is not universal as, for example, many trees do not die of old age, and some animals do not die of it. It is very ‘malleable’ and there is no known scientific limit, such as the speed of light. We only need to achieve longevity escape velocity: if we gain a year each calendar year of added life expectancy, we will no longer die of old age.
He said that medicine is progressing against cardiovascular disease and cancer but poorly against neurodegenerative disease.
The elephant in the room is that even when people that die of flu, TB or even accidents, it’s often because they are weakened by age. Each year, we gain two or three months of average healthy life expectancy, but maximal longevity is not currently rising at all.
We need a paradigm shift – people must understand that probably it is possible to stop or very much slow down senescence. The problem at the moment is like the fable of the fox and the grapes – people tell themselves they don’t want it, because they are not convinced it’s possible. We already aim for more equality between genders and the rich and poor and people of different origins – so we need now more equality between those advancing in age and others. If it is possible to help them we have a duty to do it and make the technology available to those that want it.
One positive development in France is that many people are trying to put together all of the databases concerning DNA for scientific research.
Edouard Debonneuil said that it is possible to increase the lifespan of nematodes by ten times and by 70% in mice – and recent French research had shown that it is possible to extend the lifespam of lemurs by 50%, including huge drops in cancer rates. The latter was conducted by Pifferi et al in 2018 and concerned caloric restriction.
The question is, why is there dramatic progress in animal studies and so little in humans? However, numbers of articles and funding are increasing in terms of looking at aging as a root cause of disease, and pharma companies are starting to test promising compounds.
Anton Kulaga spoke of the need to bring industry, NGOs and academia together in this fight. One idea had been to apply for EU funding for a networking grant with this aim (a COST proposal on solutions involving the biology of aging). He said that, together with Ilia Stambler and others, they had tried and failed several times and that they keep trying. They will shortly know the results of their latest attempt.
As he explained, at first in 2013, there were 23 proposals and 14 countries involved, and now there are 72 members (labs, industry and NGOs) and 31 countries. Working groups have been looking at bottlenecks in the process such as availability of technology, data and biomarkers. In March, they plan to do a datascience hackathon that will try to apply natural language processing techniques to the increasing number of research papers coming out in the life extension area. There will also be a conference in Hong Kong in June, bringing together aging research, synthetic biology, regenerative medicine and bioinformatics together to create synergy.
He explained that some members of the COST network are developing different projects, such as a rejuvenation roadmap pipeline to try to monitor which companies are at what stages in which aspects of aging. He also said that another way to speed things up is to foster links between experts in diseases and experts in aging.
Edouard Debonneuil said that it is important to bring researchers and businesses together. Investors are starting to take an interest in the area. He said he is working on creating a ‘longevity megafund’. One aim is to interest pension funds, so they have a stake in this area, as opposed to potentially opposing it. He stated that the fastest route is to invest in using existing drugs and targeting new therapies with them, as well as new molecules and innovative approaches like thymus regrowth and regeneration therapies.
Didier Coernelle said that Josh Mitteldorf of Washington University has an interesting project to test around 20 products and combinations of products.
Didier Coernelle and Dr. Bischof gave opposing views about the role of start-ups, with the former saying public support was important rather than a multitude of start-ups in which people put profit first, whereas Dr. Bischof said that we need a more American attitude and to encourage people to try to make money in the field. He said that making money is not bad, because if the research is done, something comes back to the community.
Sebastian Aguiar of Apollo Ventures, which is based in Hamburg (with offices in New York, Munich and Oxford), said during a break that Apollo has built up a team of around ten people “scouring the globe for translationally relevant projects in terms of geroscience”.
Most known geroprotective molecules are natural products or derived from them: metformin, rapamycin and its analogues, resveratrol and sirtuin activators, and NAD, which is a metabolite. Based on this rationale, we have created the largest geroprotector screening company in the world to identify molecules that extend healthy lifespan across model organisms, and we have identified one recently with Guido Kroemer and Frank Madeo, who have demonstrated in the past that spermidine extends healthy lifespan and aspirin, and other small molecules.
We have identified a new one, still confidential, which will be published in one of the Nature journals soon, derived from a Japanese longevity herb that’s been used for hundreds or thousands of years. It’s a novel mechanism caloric restriction mimetic; it enhances autophagy and autophagic flux, extends lifespan in yeasts, worms and flies, and is protective in mouse models of disease. In the literature, autophagy enhancement has been quite consistently shown to help protect against diseases of old age, including, in particular, protein aggregation diseases, including neuro-degeneration but also metabolic syndrome-related diseases. If you over-express ATG5, a critical autophagy gene, mice live about 17% longer than median lifespan, they are resistant to diet-induced obesity, and their metabolic profile is as a young mouse. So, we are interested in the cardio-metabolic diseases for the compounds coming up. The company is called Samsara Therapeutics and will be publically announced in a few months. For the Japanese substance, we are performing medicinal chemistry to optimize its properties, but we will be screening thousands of suspected geroprotectors and improving their properties.
He also said that a meeting would be held on November 5 with UK government officials to increase their awareness of geroscience and increase UK funding for studying the biology of aging. John Bell, regius professor of medicine at Oxford, has issued a report saying that the UK should prioritize “striking its own path” in anti-aging expertise after Brexit, especially as dementia is a major cause of death in the UK and there are no effective therapeutics for Alzheimer’s. “The amyloid hypothesis has dominated for 40 years, but it makes sense to take a totally new approach – slow down aging or reverse the pathology of aging, or repair the damage that causes aging, as a new approach,”
During a break, Paul Spiegel of ILA and LEAF said that he would shortly be visiting San Marino, where he hopes to encourage that country to set up a new treatment and research center on aging. He said that the regulatory framework of the microstate allows for more flexibility than in the countries of the EU.
Dr. Dmitry Bulavin, of Inserm and Ircan, gave a controversial talk about disappointing findings related to senescent cell removal from certain organs in mice, especially the liver.
He said that it is well-known that senescent cells build up in the aging body and “contribute to the aging phenotype” and that his lab has looked at how to delay senescence to delay aging; however, he followed this up with:
Now, we’re learning that it is probably a very difficult task because there are multiple mechanisms contributing to senescence and multiple cell types, so it will be extremely challenging to delay senescence in all possible types and in response to all factors.
So, he said that rather than delaying it, another approach is to eliminate senescent cells, which his lab has worked on for a decade now.
He explained that the expression of the P16 gene was found to be the best marker of senescent cells in mouse studies. However, there is a massive build-up of these cells in aged mice, so removing them at that stage may be dangerous to the animal due to the abundance, so Dr. Bulavin’s team looked at how to start removing them early in life, allowing the body to replace the cells.
“We wondered if they were going to live forever, but unfortunately it was the opposite,” he said. At around 10 months old, the mice became ill and had to be euthanized. The removed cells were not replaced by neighboring healthy cells but by extracellular matrix (collagen). Therefore, they looked at removing senescent cells in one-year-old mice after they had already built up, but there were indications that doing this harms their blood tissue permeability.
So far, their studies have shown that removing senescent cells, either in a continuous or a ‘transient’ way, seems to have detrimental effects. He suggested that the future for extending lifespan may be to go back to delaying senescence and finding new ways to do that. Reprogramming of senescent cells to remove their detrimental effect on aging may be the answer.
An audience member asked how he explains the contrast with the more positive Van Deursen results regarding the removal of senescent cells, and he said that he had not compared the studies and could only guess. He also could not comment on the efficacy of senolytics, but he would guess that there would be replacement by collagen as occurred in his research.
Dr. Bischof said that it was not certain that the P16 cells that were being removed in this study were actually senescent at all.
Didier Coeurnelle said afterwards that Dr. Bischof told him that the research appeared to relate to a very specific type of cell and was, as of yet, unpublished.
Prof. George Garinis from the University of Crete discussed of research related to inflammation, which he said needs the presence of damage and sugar. He noted that inflammation in itself can be a good thing and helps you survive stress. “Many babies would have died if they didn’t have inflammatory responses.” However, he explained that if you accumulate DNA damage, you end up with a chronic inflammatory response.
Dr. Valery Krizhanovsky of the Weizmann Institute in Israel said that senescent cells are needed for tumor suppression and limiting tissue damage and fibrosis and that they also have a role in embryonic development. Senescence is needed in the short term, but accumulation of senescent cells has a pro-inflammatory effect and can promote tissue aging and tumorigenesis; however, even in later life, there are some positive effects. He said that we have to learn to decouple the positive effects from the negative ones.
One of his lab’s studies on mice with accelerated aging found that eliminating senescent cells with a drug extended median lifespan.
One problem in aging is that the immune system works less well, which contributes to accumulation of senescent cells, so modification of the immune system – senescence immunotherapy – could be an even more promising avenue. Referring to Dmitry Bulavin’s talk, he said that it is unclear if all P16+ cells are senescent and that not all senescent cells are P16+.
Dr. Jackie Han of the Chinese Academy of Sciences said that her lab has been studying changes in the face as a marker of how quickly someone is aging. “Two people of different chronological age can have totally different biological age,” she explained. Her lab initially collected 3D images of 332 people aged between their 20s and 60s using a special camera that takes six angles at once. The lab identified components related to age and age, including a droop of the eye corners, protrusion of the lower cheek, and shrinkage of the forehead. Her team also did blood analysis and made use of the GenAge database of aging-related genes to do comparisons with the facial aging factors.
Her team was also able to compare facial aging factors with disease – people with diseases usually showed accelerated aging, which was described as a positive age-diff (looking older than average for their age). However, two cardiovascular patients showed decelerated aging. The difference was related to what drugs they were taking. Not taking drugs was related to increased aging, but three drugs were associated with slowed aging, and one of these drugs has now also been shown to increase lifespan in C. elegans. Certain health conditions are associated with certain facial changes, including depression, fatty liver, high cholesterol.
She explained that a ‘facial clock’ analysis is very cheap and takes two minutes per person. Her team has, so far, scanned 10,000 people. Facial age seems to be a better indicator of longevity than chronological age.
So far, her research has been on Asians. Her team studied four Caucasians, and one who was on a calorie-restricted diet had very decelerated aging; they will now be doing two large cohorts of Australians. Metformin had no effect on the face. Exercise helped, and eating internal organs had a negative effect.
Dr. Joao Pedro de Magalhaes of the University of Liverpool said that years ago, he started a collection of tools and databases called Human Aging Genomic Resources, which now has hundreds of thousands of users and visitors and 100 citations a year; his group also has posted news about the biology of aging on Facebook and Twitter.
One of the first databases was GenAge, of aging-related genes, that is ones that when you genetically-manipulate them – silencing, mutation, over-expression, knock-out… – it has a significant impact on the aging phenotype or on longevity. We know over 2,000 genes in total, including hundreds of genes impacting aging in C elegans, including a 10-fold increase in lifespan by changing a single gene. We know 100 genes in mice, including one creating 50% increase in lifespan with a single gene manipulation.
It’s a huge advance, but there are complex ways in which genes interact with each other and the environment, which is why we need computational systems biology approaches to better understand the mechanisms and how to intervene in aging – to understand the whole from its parts.
There are both pro and anti-longevity genes. With pro-longevity ones, if you over-express it, it increases lifespan or if you decrease it, it reduces it. All aging-related genes are together called the gerontome. They are now looking at links between aging and aging-related diseases at the genetic level. The link is often genes associated with immune responses and inflammatory processes.
Last year, the project released CellAge, a database of human genes associated with cell senescence. It found a strong overlap between genes associated with cancer, aging, and cell senescence.
There is a large project in the UK called UK Biobank, which has material from hundreds of thousands of individuals, and it is making use of this.
Anton Kulaga said that his lab (as part of the Gerontomics Project) has been looking to learn from long-lived animals, such as the bowhead whale, which can live for more than 200 years. His lab found a high similarity between long-lived species in the expression of genes related to longevity and cancer prevention, such as DNA repair and maintenance, immune response, tumor suppression, and stress response. The lab found that pro-longevity genes are transcribed more and expressed in greater amounts than anti-longevity ones in all species, but this pattern is clearer in long-lived animals. Using computers, his lab wants to find combinations of genes that extend life in many different species and ultimately that may be relevant to humans.
Dr. Paul Hofman of Nice Sophia Antipolis University talked about OncoAge, a consortium of around 1,000 hospital clinicians and university researchers fighting age-related pathologies. Founded in 2016 and based in Paris, Lyon and Nice and working in conjunction with private partners, it is an integrated project of care, education and research concentrated on age-related diseases, especially lung diseases, head and neck diseases, and neurodegenerative diseases. The consortium seeks to define clinical features and biomarkers shared by cancer and other age-related pathologies so as to develop new therapeutic targets and better prevention strategies.
Examples of its work include pioneering work on lung cancer screening – one of its projects found that blood tests can find ‘sentinel circulating tumor cells’ before anything shows up on a CT scan and are testing this further with a group of 700 smokers. Another project is a lung cancer biobank.
Dr. Ilia Stambler and Dr. Elie Mizrahi said that they have been doing research in Israel to develop new methods to evaluate multi-morbidity, such as from high blood glucose. Dr. Stambler also explained that functional measurements, such as cognitive functional assessment, were found to be more predictive of multi-morbidity than biomarkers.