Researchers have been trying to find out how to stop the formation of scars for decades, and now, thanks to a new mouse study, they are one step closer.
Scars are a fast but poor repair
Many of us have scars of one kind or another from accidents or surgery. As unpleasant as they are, the problem of scarring also goes beyond cosmetic concerns. Scar tissue is a poor substitute for healthy skin, as it lacks sweat glands and hair follicles and is structurally weaker and less flexible than skin.
Scarring occurs as an emergency response to injury to rapidly close an opening in the skin. Scar tissue forms much faster than regular skin is able to grow, and so it is chosen as the fastest way to respond to injury and prevent infection or fatal blood loss. Unfortunately, while scar tissue is a fast way to address trauma, it leads to an imperfect repair that can impair normal appearance and function.
In a new study, a team of researchers at Stanford have found out more about why we scar after injury [1]. They have also learned that by interrupting key cell signals during the healing process, wounds can be healed without scarring and are indistinguishable from healthy skin.
The researchers noticed that during skin repair, tension played a key role in the formation of scar tissue. The more tension there is on the wound, the more likely it is that scar tissue will form. A good example of this is when humans are in the fetal stage and scars do not form; this is because fetal skin is jelly-like and lacks the tightness that skin takes on when we are older.
The team showed that by lowering the tension that stretches the wound, the formation of scar tissue is reduced.
Why tension matters in scar formation
Why does tension in the skin around a wound cause scarring in the first place? To answer this, the researchers focused their attention on a gene called Engrailed-1, which facilitates the creation of a specific protein found in fibroblast cells, a type of cell that contributes to scar tissue formation.
They discovered during their experiments that there was a subpopulation of these fibroblasts in the skin that do not express the Engrailed-1 gene normally but begin to do so during the formation of scar tissue.
They then explored how tension might be involved in turning on the Engrailed-1 gene. It has been known for many years that cells can sense their environment, which includes mechanical stresses and tension. Perhaps most interestingly, there are also ways to impair a cell’s ability to sense its environment, and this made the researchers consider doing this to prevent scarring.
Starting with fibroblasts that do not normally express Engrailed-1, the team created three different kinds of environments and allowed the cells to grow in them. There was a culture on a soft gel that created no tension on the growing cells, a culture on a regular plastic dish where there was surface tension, and a culture on the same plastic dish but with a chemical to prevent cells from detecting the presence of tension in the environment.
The results were that cells in the soft gel did not express Engrailed-1, the ones on the plastic dish did, and the ones inhibited from sensing tension also did not express Engrailed-1.
Healing wounds without scarring
This was also confirmed in mice; when tension was applied to healing surgical wounds, there was an increase in the number of cells expressing Engrailed-1 and thus the formation of thicker scar tissue.
Using the drug verteporfin, which is used to treat certain eye conditions and which can block cells from sensing tension and mechanical stress, mice were given anesthesia and surgical incisions were made. Mechanical tension was applied to the wound while administering verteporfin to the healing wound
The results were a mirror of what was seen in the cell experiments. The mouse skin that healed with verteporfin administration looked like normal healthy skin. Indeed, upon examination with a microscope, the skin had normal glands and hair follicles were present in the area of healed skin; normally, this does not happen in scar tissue. The healed skin was structurally as strong as normal skin, and an artificial intelligence algorithm compared many images of healthy skin to the ones healed with verteporfin and could not find any differences.
The next step for the researchers will be further studies in other animals; if successful, a clinical trial will almost certainly follow.
Wounds in adult mammals typically heal by forming fibrotic scars. Mascharak et al. found that a specific population of skin fibroblasts (Engrailed-1 lineage–negative fibroblasts) activate expression of Engrailed-1 and turn on profibrotic cellular programs in response to local tissue mechanics in wounds (see the Perspective by Konieczny and Naik). When mechanical signaling was inhibited in these cells (using either genetic deletion or small-molecule inhibition), skin wounds in mice no longer formed scars but instead healed by regeneration, restoring skin with normal hair follicles and glands, extracellular matrix, and mechanical strength.
Conclusion
This is confirmation that the formation of scar tissue can be prevented, and it opens the door for interventions against other kinds of scarring, such as fibrosis, a common age-related affliction. It may also be possible to combat cardiac scarring after a heart attack. There are also cosmetic applications, and they could spark wider public interest if such a therapy was available after injury or surgical scarring.
We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
[1] Mascharak, S., Davitt, M. F., Griffin, M., Borrelli, M. R., Moore, A. L., Chen, K., … & Longaker, M. T. (2021). Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring. Science, 372(6540).
Date Posted: April 29, 2021
Comments Off on Smelling Food Undermines Dietary Restriction in Nematodes
Experiments by researchers in China and the US have shown that the smell of food is enough to reduce the lifespan gains caused by dietary restriction in nematodes. By unraveling the genetic and neurological network behind this, the team found evidence that the same might hold true in mammals.
Dietary restriction is more than a diet
Dietary restriction is one of the most effective longevity interventions, increasing lifespan and improving health in a wide range of creatures, including yeast, fruit flies, mice and primates. While there is no conclusive evidence that dietary restriction increases human lifespan, many people experiment with caloric restriction or intermittent fasting because of the expected health benefits.
Despite the widespread effectiveness of dietary restriction, the mechanisms linking it with health and longevity still aren’t fully understood. The nutrient signaling pathways involving AMPK and mTOR are clearly involved, but other interacting pathways or players in the process remain to be discovered. There is evidence that non-nutrient components of food can also affect aging. For example, a 2007 study showed that “nutrient-derived” smells can affect lifespan and block the benefits of dietary restriction in fruit flies [1] .
The power of smell
In the new study, researchers grew C. elegans nematodes in petri dishes with and without bacteria, which is what they eat. Some of the plates also had a thin layer of bacteria on the lid, so the nematodes could smell them but couldn’t eat them. This had no effect on lifespan for the nematodes with free access to bacteria, but in the dishes without bacteria, it caused a 50% decrease in the longevity gain from dietary restriction. In a nutshell, the smell of bacteria offset some of the lifespan extension caused by dietary restriction.
The team then carried out a series of experiments using loss-of-function mutants, neuron activity measurements, and cell-specific depletion or overexpression of genes, which allowed them to piece together the neural circuit involved. The signal is carried through a sequence of neurons from the brain to the intestine – interfering with any of the neurons in the link blocked the effect of the food smell – and is mediated by the neurotransmitter octopamine, which is the invertebrate homolog of norepinephrine. Octopamine affects lifespan by regulating the energy sensor AMPK In the intestine.
There are more details about the pathway in the study, but the most interesting point is that the researchers tested whether this signaling link is also present in mammals. They studied cultures of mouse cells that are functionally similar to the nematode intestine and showed that norepinephrine activates AMPK via the same signaling pathway. Whether this is linked via neurons to the perception of smells remains an open question, let alone whether that could alter the longevity benefit of dietary restriction.
The role of food nutrients in mediating the positive effect of dietary restriction (DR) on longevity has been extensively characterized, but how non-nutrient food components regulate lifespan is not well understood. Here, we show that food-associated odors shorten the lifespan of Caenorhabditis elegans under DR but not those fed ad libitum, revealing a specific effect of food odors on DR-mediated longevity. Food odors act on a neural circuit comprising the sensory neurons ADF and CEP, and the interneuron RIC. This olfactory circuit signals the gut to suppress DR-mediated longevity via octopamine, the mammalian homolog of norepinephrine, by regulating the energy sensor AMP-activated protein kinase (AMPK) through a Gq-phospholipase Cβ-CaMKK-dependent mechanism. In mouse primary cells, we find that norepinephrine signaling regulates AMPK through a similar mechanism. Our results identify a brain–gut axis that regulates DR-mediated longevity by relaying olfactory information about food abundance from the brain to the gut.
Conclusion
This is a great example of the value of basic research. C. elegans is a tractable system for investigating this kind of question, and it’s well-characterized enough that the researchers could tease apart all the many components linking food scents with lifespan. That would have been incredibly difficult – if at all possible – in a model mammal system, let alone in humans. The team then built on that to show that the same thing could happen in mammals, opening the door to lots of interesting questions and experiments. For example, which odors are important? What about other sense modalities, like sight? While we’re a long way from being able to say that the same thing happens in humans, the idea that lifespan could be extended by manipulating the perception of food is certainly appealing.
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BioAge Labs is off to a fast start in 2021, with two drugs in its pipeline now undergoing clinical trials and a third planned to start in the near future.
After a $90 million Series C funding round closed late last year, BioAge has moved quickly to start the new year. Like most longevity companies, BioAge utilizes broad anti-aging pathways to target specific age-related diseases. BioAge has a unique proprietary biobank of longitudinal data and AI platform for identifying longevity targets. The company’s strategy specifically involves licensing “de-risked” drugs that have already been shown safety and target engagement in a human clinical trial.
In March, BioAge launched a phase 2a clinical trial for unexplained anemia of aging. Its drug BGE-117, which was licensed from Taisho, inhibits an enzyme that breaks down hypoxia-inducible factor: a transcriptional factor that has been shown to extend lifespan in preclinical studies. Shortly after, BioAge announced another phase 2 trial, this time for COVID-19 in patients over 60 years old. BGE-175, licensed from Shionogi, inhibits the PGD2 DP1 pathway, which was identified by its AI platform to be involved in immune aging and reduced COVID-19 mortality in aged mice.
Going mainstream
Dr. Kristen Fortney, CEO of BioAge, kicked off the year presenting at the J.P. Morgan Healthcare Conference, one of the biggest annual biotech conferences in the US. Earlier this month, BioAge also announced a licensing agreement for BGE-105 with Amgen, one of the world’s largest independent biotechnology companies. BGE-105 is an APJ agonist similar to the naturally occurring apelin, a peptide that decreases with age in both rodents and humans. Apelin promotes muscle formation, activates AMPK-dependent mitochondria biogenesis, promotes autophagy, and decreases inflammation in aged mice [1].
BioAge plans to start its first clinical trial with BGE-105 in the first quarter of next year. Although the drug has already been shown to be safe in a small number of individuals, the study will be a Phase 1 pharmacodynamics study comparing its effects to apelin. While BioAge’s platform has identified the APJ pathway as one that may broadly increase longevity, the drug’s first indication will likely be specifically for sarcopenia or recovery from extended bed rest due to surgery or trauma. Dr. Fortney remarked, “The licensing agreement represents a major milestone toward our vision of developing a pipeline of treatments that separate growing older from disability and disease, dramatically improving the quality of life as we age.”
Conclusion
More than ever, longevity companies are poised to begin collecting and reporting clinical trial data. It’s an exciting time, but it is important to remember that a majority of biotech startups seem most promising just before testing their therapeutics in humans. BioAge’s strategy is certainly encouraging, as it uses an invaluable dataset, an AI-driven approach, and therapeutics with previously established safety profiles. Its ongoing trials in immune and hematopoietic aging, and newly licensed drug for muscle aging, position BioAge as a top longevity company to follow.
We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
Researchers from the University of Hong Kong have found that qigong, an ancient Chinese mind-body practice, improves cognitive abilities, lowers inflammation, and increases the size of the hippocampus in elderly subjects [1].
A value to tradition
Scientists agree that if we want to live longer, exercise is still one of our best options. It has been shown to have positive effects on almost every aspect of aging, including age-related cognitive decline [2], which has been extremely resilient to medical interventions.
In ancient times, when people did not have much choice, physical and mental practices were a widespread healing and prevention tool. These practices, which include yoga, meditation, tai chi, qigong, and many others, had been largely ignored or ridiculed by the Western scientific community for the better part of the last century. After all, it was a period when conventional medicine was making great gains against infectious and many other diseases, and the average life expectancy was constantly rising.
However, some age-related diseases emerged as formidable enemies, and the average life expectancy in developed countries has plateaued since then. Age-related cognitive decline is a field where very few inroads have been made. This has been a source of frustration for longevity scientists: currently, it seems that even if we conquer other age-related killers, such as cancer, people would still be succumbing to the unstoppable advance of age-related cognitive decline.
The attitude towards traditional practices began to change in the 1980s, with many educated Westerners, including scientists in the medical field, turning their attention towards meditation. Since then, numerous studies have confirmed that meditation can attenuate depression, stress-related health effects including inflammation [3], and even age-related cognitive decline [4]. After all, there is nothing spurious in the idea that the mind can be exercised just like muscles.
Qigong: mild and “space-saving”
Qigong is a traditional Chinese practice that combines many aspects of meditation with mild exercise. This last part makes qigong especially suitable for the elderly who often stop being physically active when usual types of exercise, such as running or hiking, become burdensome. This exacerbates health problems and accelerates the advance of frailty.
The authors of this new study note that quarantines triggered by the COVID-19 pandemic have further complicated things by rendering unattainable many physical activities on which people normally rely. Qigong, on the other hand, requires little space and can be practiced indoors.
Mind over body
For 12 weeks, the scientists studied two groups of about 25 people each: a study group that attended qigong sessions along with a control group where qigong was replaced with a similar amount of stretching exercises. Several parameters were measured before and after, including information processing speed, sustained attention, and hippocampal volume (hippocampal shrinkage has been associated with age-related cognitive decline) [5].
The researchers also analyzed the levels of interleukin-6 (IL-6), an inflammatory cytokine strongly linked to age-related neural inflammation and degeneration [6]. IL-6 levels in circulation have been shown to be inversely related to processing speed performance [7].
The results of the study show that subjects in the qigong group benefited from a statistically significant increase in information processing speed and sustained attention while their hippocampi became larger and IL-6 levels dropped. None of these effects were recorded in the control group.
Further analysis of the results revealed correlations between the parameters. For instance, in individual subjects, increase in hippocampal volume was linked to increase in sustained attention, while reduction in IL-6 levels correlated strongly with gains in processing speed.
A good start
The researchers also tested the subjects’ working memory but did not find any substantial correlation with the training. It could mean that qigong does not help to attenuate age-related memory loss, but the authors suggest that the short duration of the experiment might be responsible. Qigong is a complex practice, and 12 weeks might not be enough to reveal all its benefits.
The authors also note that in this study, the effects of qigong were compared to those of mild stretching exercises and not aerobic activity, which might have been even more effective. However, strenuous aerobic exercise might not even be an option for many elderly people.
The small sample size is yet another factor that might have affected the results. It is not uncommon for medical studies to be done on small samples, but the overall volume of research on qigong’s effects is still minuscule, which makes it impossible to interpret this study in the context of other similar studies or conduct a meta-analysis. Still, it is probably a good start.
Conclusion
There is a consensus emerging that traditional mind and body practices should be given a chance to prove themselves under rigorous research. Our growing understanding of neuroplasticity confirms that the human brain can be changed by experience. Hence, traditional practices aimed at doing just that, such as qigong, might prove helpful in slowing age-related cognitive decline, at least until science can provide a more robust alternative.
We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
[1] Qi, D., Wong, N. M., Shao, R., Man, I. S., Wong, C. H., Yuen, L. P., … & Lee, T. M. (2021). Qigong exercise enhances cognitive functions in the elderly via an interleukin-6-hippocampus pathway: a randomized active-controlled trial. Brain, Behavior, and Immunity.
[2] Horowitz, A. M., Fan, X., Bieri, G., Smith, L. K., Sanchez-Diaz, C. I., Schroer, A. B., … & Villeda, S. A. (2020). Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain. Science, 369(6500), 167-173.
[3] Rosenkranz, M. A., Davidson, R. J., MacCoon, D. G., Sheridan, J. F., Kalin, N. H., & Lutz, A. (2013). A comparison of mindfulness-based stress reduction and an active control in modulation of neurogenic inflammation. Brain, behavior, and immunity, 27, 174-184.
[4] Gard, T., Hölzel, B. K., & Lazar, S. W. (2014). The potential effects of meditation on age-related cognitive decline: a systematic review. Annals of the New York Academy of Sciences, 1307, 89.
[5] Dawe, R. J., Yu, L., Arfanakis, K., Schneider, J. A., Bennett, D. A., & Boyle, P. A. (2020). Late‐life cognitive decline is associated with hippocampal volume, above and beyond its associations with traditional neuropathologic indices. Alzheimer’s & Dementia, 16(1), 209-218.
[6] Bradburn, S., Sarginson, J., & Murgatroyd, C. A. (2018). Association of peripheral interleukin-6 with global cognitive decline in non-demented adults: a meta-analysis of prospective studies. Frontiers in aging neuroscience, 9, 438.
[7] Bott, N. T., Bettcher, B. M., Yokoyama, J. S., Frazier, D. T., Wynn, M., Karydas, A., … & Kramer, J. H. (2017). Youthful processing speed in older adults: genetic, biological, and behavioral predictors of cognitive processing speed trajectories in aging. Frontiers in aging neuroscience, 9, 55.
When you discuss any major issue, sooner or later someone will say it: there are more urgent issues than whatever it is you’re advocating for. Sometimes it may be true; other times, and probably most of the time, it’s a logical fallacy known as appeal to worse problems (or “not as bad as”, or even “fallacy of relative privation”).
For example, say you’ve got two issues, A and B, that cannot possibly be both dealt with at the same time; if A is life-threatening and B isn’t, well, then I think it’d make sense to reply “there are more urgent issues” to whoever suggests B should be taken care of first. However, all too often, this answer is abused to play down the importance of a problem that doesn’t happen to be one’s personal favourite—and yes, I’ve seen this happen with rejuvenation therapies.
Near-infinite regress
If the appeal to worse problem reasoning was iterated for all problems humanity has to face, we’d end up with over seven billion people all concerned only about the absolute worst problem and entirely neglecting the others. I really don’t think we could ever get everyone to agree on what human problem is the worst, but even if we could, second and third place alone would probably be enough to wipe us off the face of the Earth, if we turned our back on them to focus only on the winner of the “worst catastrophe of all times” contest.
It’s clear beyond doubt that this is not a wise plan of action, and perhaps more importantly, it’s not necessary; we have more than enough people and resources to face several issues at once, so there’s no reason to let children in developing countries starve while we fix pollution, nor is there a reason to halt research against malaria while we research how to bring aging under medical control.
Why should aging be a “second-class” priority?
My mentioning of malaria and aging together is no accident; it’s an example from a real-life conversation I had that stuck with me. During the conversation, it was suggested that resources and effort would perhaps be better spent on malaria than rejuvenation biotechnologies. To this day, I still can’t help wondering, on what grounds this would be the case?
Unlike malaria, starvation, and many other global issues—all of which, make no mistake, are extremely serious and deserving of attention—very few resources are dedicated to the problem of aging, and nearly none to rejuvenation biotechnologies. Without initiatives such as SENS, lifespan.io, etc, and the efforts of few philanthropists, it’s likely that no rejuvenation research would take place at all, and the research itself is often even opposed by some.
On the other hand, efforts to solve more traditional problems, such as the aforementioned malaria and starvation, enjoy the endorsement of the world at large, the full attention of FAO, WHO, and various NGOs, and the financial support and personal commitment of personalities such as Bill Gates—who recently announced he now wants to tackle Alzheimer’s disease, which is extremely good news.
If we’re talking just numbers, I really see no reason why the few resources currently devoted to rejuvenation should be diverted to other, already better-funded issues, and there’s no reason why currently unallocated resources that could be used for the largely neglected field of rejuvenation research should instead go towards solving other, more popular problems.
I don’t think that trying to establish whether malaria is a more serious problem than aging would be very respectful of either issue; both cause tremendous suffering, and both kill. However, if you look at the numbers, it’s easy to see that aging causes, by far, more suffering and deaths than not only malaria but all other causes of death put together: every day, roughly 100,000 people die of age-related causes; that’s two-thirds of the total deaths happening around the world in a day, which is around 150,000. Malaria, and all the other causes of death, each cause only some of the remaining 50,000 deaths, so it’s absolutely obvious that aging wins hands down. Also, causes of death other than aging concern only part of the population, whereas aging concerns every single human being, directly and indirectly.
Does this mean that we should stop worrying about malaria or starvation and worry only about aging? Not at all! If we did that, malaria might spiral out of control and turn into a pandemic, and even if it didn’t, it might cause far more suffering than it already does and claim even more lives than now. However, the lives of people sick with malaria are just as important as those of geriatric patients, and both deserve the best we can give them. Refusing to put resources into rejuvenation research would mean deeming the lives of the elderly less important than those of other patients, and their suffering less worthy of our attention, which would be just as horrifying as the opposite.
Research is always research
Whether or not we think there are more urgent problems than aging doesn’t change the fact that rejuvenation research is nothing more and nothing less than medical research. Human biology being the entangled mess that it is, unexpected connections are paradoxically to be expected, and research on the fundamental mechanisms of aging—which involves studying mitochondria, stem cells, cancer, genomics, and many other things—can and does shed light on biological phenomena and pathologies that may happen well before old age. If aging research was neglected entirely, progress in other areas of medicine would likely be not as fast as it could be.
By the year 2050, one in four Europeans will be aged 65 or over, which presents a number of challenges and possible opportunities for Europe’s rapidly aging society. To this end, the European Commission published the “Green paper on ageing – Fostering solidarity and responsibility between generations” back in January to encourage a broad policy debate on the topic.
As part of this initiative, the EU opened the topic up for public consultation and further discussion. They have published a green paper on aging which you can also find detailed below.
The silver tsunami is coming, and we are not ready
Unfortunately, like many other similar initiatives in the past, this green paper makes no mention of the potential of therapies that seek to target the aging processes directly. In general, world governments still remain largely oblivious of the role of medical research in the future of aging and how interventions might slow or even reverse it.
This is a real problem, because not only do green papers like this one cost considerable amounts of money to produce, they also contribute towards shaping future societal views and strategies regarding aging.
An aging population is going to become an increasing problem as we approach 2050, especially with many countries seeing a large decline of fertility and some even entering negative population growth. Some countries could soon face a situation where there are more older people than young and will struggle to cope with the burden on the healthcare and economic systems that this will bring. This is sometimes called the silver tsunami.
The growing number of old people relative to the overall population will put increasing pressure on pensions, socialized healthcare systems, and other entitlement systems. If something is not done to solve this problem, the situation will become unsustainable and socio-economic systems will be unable to cope in their current forms.
This is why it is absolutely critical that the inclusion and development of therapies to treat the causes of aging, to slow, delay, or even reverse aging must be part of that solution.
The green paper falls short of what needs to be done
This green paper is another disappointing example of just how much work our field has ahead of it in order to gain a place at the table in such discussions, as it makes the same mistakes as the WHO 2015 World Report on Aging and Health and the Decade of Healthy Aging initiative. The focus is on compensating for the consequences of aging rather than addressing the problem by developing rejuvenation biotechnology. We have a lot of work to do before things start changing on the level of international policy.
We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
In a new paper published in Aging, researchers have determined that directly improving autophagy through flubendazole (FLBZ) is potentially useful in treating dry age-related macular degeneration (AMD), a disease that causes vision loss.
An accumulation of lipids
Dry AMD shares a surprising commonality with atherosclerosis. As our macrophages attack the fatty (lipid) deposits in our arteries, they accumulate 7-ketocholesterol, a substance that they are unable to properly digest. This intracellular accumulation is called lipofuscin, and macrophages that have accumulated too much lipofuscin simply become part of the problem.
In dry AMD, retinal pigment epithelial (RPE) cells accumulate their own form of lipofuscin; when it is excreted outside the cells, it forms a harmful aggregate known as drusen. Unlike macrophages that have accumulated 7-ketocholesterol, RPE cells are capable of breaking their lipofuscin down; however, in dry AMD, they fail to properly break down enough of it. As the researchers explain, RPE cells both consume and produce substantial amounts of lipids, and they break down otherwise indigestible lipofuscin through autophagy, the same self-consumption process that cells use to break down their own organelles.
Specifically avoiding mTOR inhibition
Autophagy is often mediated by inhibiting mammalian target of rapamycin (mTOR), but the researchers of this study specifically wanted to avoid affecting it. This may come as a surprise for our regular readers; as we have previously reported, mTOR inhibition is linked to immune health in aged people, and its overexpression is linked to diabetes and aging.
The researchers explain that, rather than being a positive influence, mTOR inhibition is dangerous for RPE cells because this compound plays too much of a role in their normal functioning. While excessive mTOR expression would cause these vital cells to dedifferentiate into mesenchymal stem cells [1], the tight junctions of RPE cells are useful as an overall market of their health, and this study provided evidence that mTOR inhibition causes these junctions to lose integrity. Additionally, in a previous study, rapamycin (sirolimus) offered no therapeutic benefit against dry AMD [2].
Simply put, due to the importance of mTOR in RPE cellular processes, compounds that affect its expression are the wrong tools for the job.
Affecting autophagy directly
With the dangers of mTOR in mind, the researchers sought compounds that would promote autophagy through other biochemical pathways. Five compounds were shown to improve autophagy by one metric, but only two, D4476 and FLBZ, were found to visibly increase the number of autophagosomes.
The researchers thoroughly investigated FLBZ and found multiple reasons for hope. FLBZ improved cell health as measured by tight junctions, reduced lipofuscin-like material, reduced senescence associated with lipofuscin-like material, and led to more compaction of the granules of this material, thus reducing their reactivity. Therefore, the researchers hold that FLBZ is a candidate drug for dry AMD.
Caveats
Using a mouse model for this study would have been inappropriate because the extracellular deposit known as drusen, a key feature of dry AMD that results from lipid formation, is substantially different between model mice and humans [3]. Therefore, the researchers used fetal cells instead; however, one problem with this method is that fetal tissue does not recapitulate the problems found in older people, and another is that the RPE cells are placed outside of their usual environment. As with all interventions, it is impossible to tell whether or not this technique will become a successful therapy in living, breathing humans until it has passed human clinical trials.
Conclusion
Whether or not this study leads to a therapy in humans, it certainly proves one thing: we need greater direct control over biological fundamentals and cellular processes in living beings. While influencing broad metabolic factors such as mTOR to promote downstream measures of health is a positive advance, such a strategy is clearly insufficient as an intervention against many individual age-related diseases, even autophagy-related diseases such as dry AMD.
On the other hand, if D4476 and/or FLBZ prove useful in directly improving autophagy in RPE cells, it may be useful to test their efficacy in other diseases for which increased autophagy may be an effective treatment. As FLBZ is already an established drug, approved by the FDA as an antihelminthic, we look forward to future trials of its efficacy as a treatment for dry AMD.
We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
[1] Zhao C, Yasumura D, Li X, Matthes M, Lloyd M, Nielsen G, Ahern K, Snyder M, Bok D, Dunaief JL, LaVail MM, Vollrath D. mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice. J Clin Invest. 2011; 121:369–83. https://doi.org/10.1172/JCI44303
[2] Gensler G, Clemons TE, Domalpally A, Danis RP, Blodi B, Wells J 3rd, Rauser M, Hoskins J, Hubbard GB, Elman MJ, Fish GE, Brucker A, Margherio A, Chew EY. Treatment of Geographic Atrophy with Intravitreal Sirolimus: The Age-Related Eye Disease Study 2 Ancillary Study. Ophthalmol Retina. 2018; 2:441–50. https://doi.org/10.1016/j.oret.2017.08.015
[3] Fletcher EL, Jobling AI, Greferath U, Mills SA, Waugh M, Ho T, de Iongh RU, Phipps JA, Vessey KA. Studying age-related macular degeneration using animal models. Optom Vis Sci. 2014; 91:878–86. https://doi.org/10.1097/OPX.0000000000000322
Date Posted: April 23, 2021
Comments Off on NMN Human Trial Suggests Improved Muscle Glucose Metabolism
In recent years, there has been considerable interest in the naturally occurring molecule and dietary supplement nicotinamide mononucleotide (NMN) and its potential influence on aging. While there have been numerous animal studies suggesting that it may be useful in combating some age-related decline, there has been a lack of human data until now.
In previous mouse studies NMN has been shown to improve metabolism and in particular boosts mitochondrial function, increases cognitive function in aged mice, and improves DNA repair.
Researchers at Washington University School of Medicine in St. Louis have published the results of an NMN human trial that suggest clinically relevant results in people given NMN. This is the first randomized clinical trial to examine the effects of NMN administration on human metabolism [1].
This small trial saw 13 women with prediabetes given 250 mg of NMN orally each day for a period of 10 weeks; the remaining 12 participants were given a placebo.
Administration of NMN appeared to improve the ability of insulin to increase glucose uptake in skeletal muscle. This uptake is typically dysfunctional in people experiencing prediabetes, type 2 diabetes, or obesity. Insulin boosts glucose uptake and storage in muscle, and people with insulin resistance have an increased risk of developing Type 2 diabetes.
The researchers also observed that there was an increased expression of genes associated with muscle structure and remodeling in participants given NMN.
The researchers reported that administration of NMN did not appear to reduce blood glucose levels or blood pressure. It also did not appear to have an impact on blood lipid profile, raise insulin sensitivity in the liver, or reduce the presence of fat in the liver. The researchers also reported that treatment with NMN did not decrease the presence of inflammatory biomarkers as it has been known to do in mice.
In rodents, obesity and aging impair nicotinamide adenine dinucleotide (NAD+) biosynthesis, which contributes to metabolic dysfunction. Nicotinamide mononucleotide (NMN) availability is a rate-limiting factor in mammalian NAD+ biosynthesis. We conducted a 10-week, randomized, placebo-controlled, double-blind trial to evaluate the effect of NMN supplementation on metabolic function in postmenopausal women with prediabetes who were overweight or obese. Insulin-stimulated glucose disposal, assessed by using the hyperinsulinemic-euglycemic clamp, and skeletal muscle insulin signaling (phosphorylation of AKT and mTOR) increased after NMN supplementation, but did not change after placebo treatment. NMN supplementation up-regulated the expression of platelet-derived growth factor receptor β and other genes related to muscle remodeling. These results demonstrate NMN increases muscle insulin sensitivity, insulin signaling and remodeling in women with prediabetes who are overweight or obese (ClinicalTrial.gov NCT 03151239).
Conclusion
While the results of this study are interesting, we should remain cautious and avoid jumping on the bandwagon just yet. These are only the initial results of what is a very small human trial, so we encourage patience here. Larger studies are required to ascertain whether NMN has beneficial effects for the prevention or management of prediabetes or diabetes in people.
Meanwhile, if you are interested in learning more about NMN and why it could potentially be important in combating aging, you may wish to dive into our summary of nicotinamide adenine dinucleotide (NAD+).
We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
People with major depressive disorder may have a biological age as much as two years greater than their chronological age, according to a new study [1]. The discovery provides a first step towards understanding the biological mechanisms that link depression to decreased lifespan.
A link between depression and aging
Depression is a serious global problem. The WHO calls major depressive disorder “the single largest contributor to global disability,” saying that it accounted for “7.5% of all years lived with disability in 2015” and is a major contributor to suicide deaths [2]. Depression is a known risk factor for a range of diseases, many of which are also associated with aging, including cardiovascular disease and dementia.
To address that question, a research team used GrimAge to estimate the biological age of 50 patients with major depressive disorder along with 63 healthy controls. The measurements were taken using DNA extracted from blood samples rather than brain tissue.
Their analysis detected accelerated aging in the samples from patients with depression, with about two years of extra aging on average. This is approximately equivalent to the amount of extra aging detected in the fMRI study, which is an encouraging sign that researchers are on the right track.
However, the amount of increased aging didn’t correlate with depression severity, lifetime days of depression, days of untreated depression, or the duration of a current depressive episode. In other words, while the patients with depression showed accelerated aging, it’s not yet clear how to predict how much acceleration an individual patient would exhibit.
The researchers also weren’t able to pin down exactly which GrimAge markers contribute to the accelerated aging measure. Two groups of markers differed significantly between the patients and controls, but the statistical significance disappeared when they controlled for other factors, perhaps because of the small sample size. A site in one of the markers has also been suggested to play a role in post-traumatic stress disorder, so it’s tempting to think that there might be a link awaiting discovery.
Major depressive disorder (MDD) is associated with premature mortality and is an independent risk factor for a broad range of diseases, especially those associated with aging, such as cardiovascular disease, diabetes, and Alzheimer’s disease. However, the pathophysiology underlying increased rates of somatic disease in MDD remains unknown. It has been proposed that MDD represents a state of accelerated cellular aging, and several measures of cellular aging have been developed in recent years. Among such metrics, estimators of biological age based on predictable age-related patterns of DNA methylation (DNAm), so-called ‘epigenetic clocks’, have shown particular promise for their ability to capture accelerated aging in psychiatric disease. The recently developed DNAm metric known as ‘GrimAge’ is unique in that it was trained on time-to-death data and has outperformed its predecessors in predicting both morbidity and mortality. Yet, GrimAge has not been investigated in MDD. Here we measured GrimAge in 49 somatically healthy unmedicated individuals with MDD and 60 age-matched healthy controls. We found that individuals with MDD exhibited significantly greater GrimAge relative to their chronological age (‘AgeAccelGrim’) compared to healthy controls (p = 0.001), with a median of 2 years of excess cellular aging. This difference remained significant after controlling for sex, current smoking status, and body-mass index (p = 0.015). These findings are consistent with prior suggestions of accelerated cellular aging in MDD, but are the first to demonstrate this with an epigenetic metric predictive of premature mortality.
Conclusion
People with major depressive disorder have a shorter life expectancy on average. While changes in aging biology certainly aren’t the only possible explanation, it’s worth exploring how the two are linked, particularly given the association between depression and many age-related diseases. By showing accelerated cellular aging in these patients and correlating depression with epigenetic changes, this research brings us closer to understanding the biological mechanisms linking depression with decreased lifespan and healthspan.
We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
[1] Protsenko, E. et al. “GrimAge,” an epigenetic predictor of mortality, is accelerated in major depressive disorder. Translational Psychiatry (2021), doi: 10.1038/s41398-021-01302-0
Spermidine is known to decline with aging, and treatment with spermidine extends lifespan across various species. While it has a myriad of potentially beneficial effects, spermidine has been most clearly demonstrated to impact autophagy and mitophagy, promoting the removal and replacement of damaged mitochondria in both mice and flies. It is one of the most highly studied longevity compounds, including in the brain, where intra-abdominal and intra-cerebral spermidine injections have been shown to enhance cognition both in aged mice and in transgenic models of neurodegeneration.
Can dietary spermidine achieve similar results?
A large collaboration based at the University of Graz in Austria has studied spermidine when supplied continuously via drinking water rather than intermittently with injections [1]. Spermidine was found to cross the blood-brain barrier in aged male and female mice. In male mice, it also moderately improved a variety of behavioral tests of cognition at an old age of 24 months.
Interestingly, female mice and male mice receiving the higher dose investigated by the researchers did not see as much positive improvements as the male mice treated with the lower dose. This suggests that more dose-response studies, particularly regarding sex differences, are needed on spermidine and cognitive function.
When the researchers delved into the mechanisms of action of their treatment, they did not find an activation of known NMDA receptor targets, which occurred in similar studies that delivered spermidine via injection. However, they did find improved respiratory capacity (a measure of mitochondrial function) in the hippocampi of aged mice and in the heads of fruit flies.
To show that this effect was mediated by autophagy, the researchers knocked out Atg7, a key gene essential to autophagy in the fruit flies. In these flies, spermidine no longer had the previously seen benefits on mitochondrial function. Similar results were seen by knocking out Pink1 or Park, genes involved in mitophagy, suggesting that these specific pathways are involved.
Spermidine in our regular diets
Finally, the researchers analyzed an existing dataset within the Bruneck study that followed the diet and cognitive function of older adults over time. Dietary spermidine intake was estimated based on self-reported food frequency questionnaires and was stable over time within individuals. After adjusting for age, sex, and caloric ratio, spermidine intake was correlated with various measures of cognitive function and reduced the odds of developing cognitive impairment.
These findings held regardless of sex, social status, and level of education, whether various adjustments were made (i.e. excluding subjects with depression) or whether the data was analyzed as continuous or if subjects were grouped into low/medium/high spermidine intake cohorts. Since spermidine also correlates with other nutrients, the authors also controlled for their results using the Alternate Healthy Eating Index. The benefits of spermidine remained significant, suggesting that the correlation goes beyond a healthy eating pattern.
The combination of epidemiological and experimental data raises the intriguing possibility that dietary SPD may be protective against cognitive decline in humans. Elevated intake of SPD has recently been shown to be safe in healthy, elderly humans (Schwarz et al., 2018). In a phase II trial including subjects with self-reported cognitive decline, SPD led to detectable improvements in cognition already after a 3-month treatment period (Wirth et al., 2018). We herein propose that dietary SPD acts in a neuroprotective manner during normal aging. The beneficial effects of SPD appear to depend on autophagy- and likely mitophagy-related processes that culminate in improved mitochondrial capacity, at least in model organisms. Accordingly, the straightforward and inexpensive availability of nutritional SPD in the human diet may provide a potent strategy to prevent the course of age-related or disease-driven cognitive decline in the general population.
Conclusion
This study provides novel data on the effects of spermidine on the aging brain when delivered through the diet. It also sheds light on its mechanisms of action for improving cognition, highlighting the role of mitophagy. Not many studies utilize flies, mice, and humans concurrently. This study’s application to all three species makes for more robust and convincing results. However, it should be noted that the cliché “correlation not causation” fundamentally applies to the researchers’ analysis of the human dataset.
There are many other factors that are impossible to control for and may also be at play. Nonetheless, this study adds to our understanding of spermidine as a therapeutic agent and further justifies its investigation in clinical trials for longevity and cognitive decline, some of which are currently ongoing [2].
We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
[1] Schroeder, S., Hofer, S.J., Zimmermann, A., Pechlaner, R., Dammbrueck, C., … & Madeo, F. (2021). Dietary spermidine improves cognitive function. Cell Reports, 35(2), 108985. https://doi.org/10.1016/j.celrep.2021.108985
[2] Wirth, M., Benson, G., Schwarz, C., Köbe, T., Grittner, U., … & Flöel, A. (2018). The effect of spermidine on memory performance in older adults at risk for dementia: A randomized controlled trial. Cortex, 109, 181-188. https://doi.org/10.1016/j.cortex.2018.09.014
Date Posted: April 20, 2021
Comments Off on B-cell Depletion Ameliorates Alzheimer’s in Mice
According to a new study, Alzheimer’s disease is connected to inflammaging, which causes B-cells to change their phenotype and hamper amyloid-β (Aβ) removal [1]. Following successful experiments in vivo, the scientists propose B cell depletion as a possible therapy.
The darker side of B cells
Alzheimer’s disease (AD) is deadly, frustratingly resilient to treatment, and highly correlated with aging. Billions of dollars and millions of person-hours have been spent searching for a cure to no avail. One of the hallmarks of AD is the accumulation of Aβ plaques in the brain, but there is an ongoing debate about whether they are a symptom or a cause of AD. So far, targeting those plaques directly has only managed to slow the disease’s progression. Given the limited success of previous approaches, every new one attracts a lot of interest.
In this paper, a group of researchers delve into the role that B cells play in AD. B cells are immune cells that, along with T cells, facilitate our adaptive immune response. Their role in AD progression has not been well researched until now, but it was found to be largely beneficial.
In their paper, the researchers reveal what they call the darker side of B cells. The group used three different murine AD models: genetically engineered mice that recapitulate AD symptoms and progression. In all models, the disease progression correlated with a marked increase in the number of B-cells in circulation and in the brain. However, when B-cell production had been genetically downregulated in these AD-prone mice, they experienced much fewer AD symptoms: better cognitive and memory abilities and fewer Aβ plaques.
The researchers then tried to achieve similar results via therapeutic B-cell depletion and found that it can be done if the therapy begins at the onset of the disease. They then endeavored to discover why and how B-cells exert two seemingly opposite effects on one disease.
Inflammaging yet again?
Our body has a built-in mechanism for removing excess Aβ. The clearance is performed by microglia and astrocytes (types of brain cells) and is normally helped by B-cells. The problem is, like many other maintenance mechanisms, this one becomes dysregulated with age, which might explain the aging-related nature of AD.
The researchers think that age-related chronic inflammation (inflammaging) might be responsible. As a result of inflammaging, microglia become sick and less effective, while the same B-cells that have been helping microglia to clear out Aβ plaques acquire an inflammatory phenotype and contribute to inflammaging in the sort of feedback loop that is often found in biology.
This additional inflammation probably outweighs B-cells’ positive effect. Moreover, experiments suggest that increased inflammation causes B-cells to start attacking microglia. This “Jekyll and Hyde” hypothesis is supported by recent research. One study, for instance, found that inflammaging can change B-cells of a certain subtype from healthy to pathogenic [2].
Further proving the point, in elderly mice with the AD phenotype, the number of Aβ-clearing microglia was significantly lower than in healthy controls; this effect was reversed, and the Aβ load was reduced, following B-cell depletion.
The researchers’ proposal – to decimate the B-cell population in the body – may seem controversial, since B-cells are an integral part of our immune system, but B-cell depletion therapy (BCDT) already exists. Initially conceived as a method of eliminating cancerous B cells, it is now successfully used against various autoimmune diseases [3], so, theoretically, nothing prevents it from being deployed against AD.
However, there is a more general conclusion to be drawn: if, as the study suggests, this chain of AD-exacerbating events is triggered by inflammaging, the ultimate answer may lie in curbing it. Longevity researchers have realized the importance of fighting inflammaging long ago, and a lot of work has already been done. This paper supports the hypothesis that inflammaging simultaneously drives many different aging-related problems.
Fortunately, we have multiple practical methods of reducing the risk of inflammaging, such as switching to healthier lifestyles. Research shows that healthy dietary practices [4] and physical activity [5] can lower the risk of AD, and inflammaging may be part of why.
Conclusion
This paper suggests an intriguing connection between Alzheimer’s disease and inflammaging. This paper shows that age-related chronic inflammation provokes a transformation of B-cells, making them harmful to the process of Aβ removal. The paper also suggests B-cell depletion as a possible therapy, but other ways of lowering inflammaging can potentially prove effective as well.
We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
[1] Kim, K., Wang, X., Ragonnaud, E., Bodogai, M., Illouz, T., DeLuca, M., … & Biragyn, A. (2021). Therapeutic B-cell depletion reverses progression of Alzheimer’s disease. Nature Communications, 12(1), 1-11.
[2] Lee-Chang, C., Bodogai, M., Moritoh, K., Olkhanud, P. B., Chan, A. C., Croft, M., … & Biragyn, A. (2014). Accumulation of 4-1BBL+ B cells in the elderly induces the generation of granzyme-B+ CD8+ T cells with potential antitumor activity. Blood, The Journal of the American Society of Hematology, 124(9), 1450-1459.
[3] Lee, D. S., Rojas, O. L., & Gommerman, J. L. (2020). B cell depletion therapies in autoimmune disease: advances and mechanistic insights. Nature Reviews Drug Discovery, 1-21.
[4] Morris, M. C. (2009). The role of nutrition in Alzheimer’s disease: epidemiological evidence. European Journal of Neurology, 16, 1-7.
[5] Meng, Q., Lin, M. S., & Tzeng, I. (2020). Relationship between exercise and Alzheimer’s disease: A narrative literature review. Frontiers in neuroscience, 14, 131.
Any discussion of rejuvenation biotechnology almost certainly includes the subject of overpopulation and the objection that medical advances that directly address the various processes of aging will lead to an overpopulated world. Such dire predictions are a common theme in many discussions involving advances in medicine that could increase human lifespans.
Overpopulation is a word that gives the simple fact of population growth a negative connotation. It implies that an increase in the number of people will harm our lives in different ways, such as famine, scarcity of resources, excessive population density, increased risks of infectious diseases, and harm to the environment.
This concern, first raised by the work of 18th century reverend and scholar Thomas Malthus, has been a constant theme in both popular fiction and early foresights related to population growth. However, is it actually well-founded? We will be taking a deeper look at the historical and present population data and showing why overpopulation is unlikely to happen.
To get you started, the X10 team has made a two-part short video series about the overpopulation concern.
What is the population, and how will it grow in the future?
Since the 1960s, both birth rate and population growth have been gradually falling. This will probably lead to a complete halt at 11 billion people near the year 2100. Here is a chart from the United Nations Population Prospects 2019 edition showing the corresponding projections [1].
Here we can see the continuous, red trend line gradually levelling out into a straight horizontal line. While the population continues to grow, it is at a slower pace than at any time since 1950. However, before talking about why population growth is predicted to stop, let’s investigate why the population is even growing.
In order to ensure population growth, the number of children born per year must surpass the number of deaths in a given country. Typically, a fertility rate index equal to 2.1 is enough for the population to renew without growing in numbers, but a higher birth rate will lead to stable population growth.
The biggest contributors to the current level of population growth globally are India and several African regions, while many countries (especially in Europe) face depopulation because of their low birth rate. Sub-Saharan Africa will account for most of the growth of the world’s population over the coming decades, while several other regions will begin to experience decreasing population numbers.
Our intuition may tell us that it is unlikely that the least developed countries would be producing most of the population; after all, the standards of living in developed countries make for better conditions to have more children. However, in reality, there are many factors that can lead to a decline in birth rate during the transition to a developed country: education (access to education for women typically postpones marriage and childbirth), unemployment (families try to control their family size to use fewer resources), and access to contraceptive techniques and cultural norms of using them, to name just a few [3].
Economic development is known to affect the time of birth; for example, recession encourages childbirth later in life [4]. National policies to combine work and family life also represent an important factor that may affect fertility rate in both directions. Globalization will “deepen” (in a world-systems theory sense) the less technologically advanced countries, making it very likely that the “higher birth rate” issue in these countries will also decline.
There is supporting evidence showing that moving to an advanced, industrialized economy changes the birth rate of immigrants. The fertility rates of immigrants to the US have been found to decrease sharply in the second generation [5]. Other studies demonstrate that the presence of immigrants does not compensate for declining birth rates [6].
Fig 4. Declining birth rate leads to gradual slow down of the population growth. World Population Prospects 2019: Data Booklet [7].
The relationship between the level of the development of a country and fertility can be seen in the next chart. It is worth noting that when the Human Development Index (HDI) becomes higher than 0.85, country development starts promoting the birth rate again [8]. However, this kind of situation is very rare, historically, and therefore not significant enough to shape global population projections.
Fig 5. Fertility vs HDI Index. Data source: United Nations Human Development Index (HDI), UN – Population Division (Fertility), 2015 Revision, Gapminder. Source
Thus, the least developed countries are more likely to have higher birth rates because people there have no reason to postpone childbirth, nor are measures for contraception widely accessible. The only factor holding back population growth in these regions may be the high level of child mortality and overall mortality due to infectious diseases and undernourishment.
With sustainable development goals focused on the solution of both problems, Africa has the potential to become the biggest human factory in our history. However, taking into account how fast fertility rates can fall because of the adoption of new technologies, this is far from certain.
Fig 6. How long did it take for fertility to fall from more than 6 children per woman to fewer than 3 children per woman? Data source: The data on the total fertility rate is taken from the Gapminder fertility dataset (version 6) and the World Bank World Development Indicators. Source: OurWorldInData.org.
But won’t we run out of space?
In all projected future scenarios for Africa, its population will continue to grow. Today, there are 7.4 billion people on Earth. We are used to thinking that this is already too much, but is that true? First of all, let’s see how much space on Earth we humans actually take up. In 2012, the team of the project “Per Square Mile” led by Tim de Chant produced an infographic showing how big a city would have to be to house the world’s 7 billion people.
The city limits change drastically depending on which real city is used as the model and what its population density is, but this still gives us an idea of how much of our beautiful planet is really inhabited and how much spare space we still have.
If the projection of population growth by the United Nations is correct, in the next 84 years, there will be about 11 billion people. This means that if all of humanity were concentrated in a land area with a population density similar to New York, it would at most occupy the size of 3 US states by 2100.
2012 2100
Fig 7. 7 bln city with population density of New York/11 bln city with the same population density. From the “Per Square Mile” project by Tim de Chant. Note: the picture at right is modified by the article authors to illustrate the potential growth. The state of Texas is about 700,000 square kilometers, which corresponds to about 7 billion people. The states of Texas, New Mexico (about 315,000 km^2), and Louisiana (about 135,000 km^2) combined represent 1,150,000 square kilometers, which corresponds to about 11.5 billion people by 2100.
Does this mean that population growth is not an issue? From the point of view of the space we humans need, likely so. However, our species’ survival is dependent on many other factors, such as the environment necessary to produce our food and other goods.
Are we going to run out of food?
We should admit that it is about fifty years too late to be concerned about extensive population growth and its consequences, such as famine, because the highest birth rate and population growth was observed from the 1960s to the 1980s. Our population grew by one billion people in just 14 years (going from 3 to 4 billion); however, no big societal or economic challenges were encountered.
Moreover, the next two billion increases in population appeared in 13 and 12 years, respectively [9], but once again, no famine caused by the deficiency of global food production followed [10]. The famines of the second half of the 20th century were provoked by how the food was distributed. Factors such as administrative incompetence of local governments, wars and natural disasters happening several years in a row played the greatest role in creating famine during this period.
Today, global society is taking measures to eradicate hunger worldwide by 2030. This is very likely to be the case, as the number of people suffering from hunger is decreasing fast. In 2012, it was one in eight, while in 2015, it was already one in nine, which corresponds to 795 million people. Below, you can see the Hunger Map by the World Food Program illustrating the progress.
If we compare the food supply in 1965 and in 2007, we can clearly see that overeating is more of a global issue than undernourishment, as in most countries, the calorie intake has grown significantly. This could not have happened if our society was suffering from food underproduction, as the food would not be available to overeat, and problems such as obesity would not be so prevalent.
Fig 9. Food supply 1965 vs 2007. Source: Gapminder statistics.
Astoundingly, this means that a population explosion has passed relatively unnoticed – all thanks to the “Green Revolution” (rapid development of new agriculture techniques, such as fertilizers, irrigation and selection). The concern that there will be a food shortage in the future neglects further technological advances such as aquaponics, hydroponics, aeroponics, vertical farming, 3D-printed housing, algae farms, and many other technologies that could provide enough food for all.
The need for more food production represents an excellent opportunity for entrepreneurs, so it is unlikely that the development process of new technologies would suddenly stop, especially taking into account the objective need for rapid changes due to environmental issues.
According to a report by the Food and Agriculture Organization of the United Nations, “Livestock’s long shadow”, in 2006, livestock represented the biggest of all anthropogenic (i.e., due to human activity and with potentially harmful side effects) land uses, taking up to 70% of all agricultural land and 30% of the ice-free terrestrial surface of the planet [11].
Scientists admit that while it is still possible to expand agricultural land in some countries in accordance with the increasing need for food, this expansion cannot go beyond the limits of the carrying capacity of our planet. The report states that livestock is responsible for about 18% of the global warming effect, 9% of total carbon dioxide emissions, 37% of methane and 65% of nitrous oxide. Water use for livestock represents about 8% of all human water use (7% of this being used for feed irrigation).
New technologies can provide solutions for the numerous environmental issues related to traditional farming. For instance, hydroponics offers around 11 times higher yields while requiring 10 times less water than conventional agriculture [12]. The energy needs of a hydroponic facility are much higher (up to 80 times more), but thanks to emerging clean renewable energy technologies, this increased demand may not be an issue [13].
Today, there are many companies engaged in the creation of lab-grown meat, such as Supermeat and Memphis Meats. Making a laboratory into a farm is beneficial in many ways, starting from less pollution and fewer greenhouse gas emissions (mostly caused by animal digestion processes).
Sterile conditions in the lab lead to decreased risk of infections and allow the exclusion of antibiotics from the process of meat production. Lab-grown meat can be designed to contain less fat or even fats and proteins with new characteristics (for instance, essential Omega fatty acids).
With less space necessary for laboratory meat production and no waste, it will be possible to ensure disseminated local production in order to cut transportation time and reduce the usage of preservatives. The same system can be used to grow fish meat as well, thus reducing the impact of fishing and fish-farming on the environment. It is interesting to note that not only meat but also other animal-derived products, such as leather, can be produced in a lab, like is done by Modern Meadow.
There are attempts to create new edible products that taste like meat but are completely without animal ingredients, such as Impossible Foods. The recently created vegan ‘Bloody Burger’ by Impossible Foods “uses 95% less land, 74% less water and emits 87% fewer greenhouse gas emissions than its cattle-derived counterpart”. By concentrating on the heme molecule, the mixture apparently “looks like meat, tastes like meat and sizzles like meat“.
These solutions are also great from an ethical point of view, as this technology can reduce animal suffering. The rate of transition to these new ways of animal product creation is widely dependent on political will and social support. It is important to note that there is also significant progress regarding access to drinking water. During the Millennium Development Goals period (1990-2015), it is estimated that, globally, use of improved drinking water sources rose from 76 per cent to 91 per cent. 2.6 billion people have gained access to an improved drinking water source since 1990.
The MDG target of 88 per cent was surpassed in 2010, and in 2015, 6.6 billion people used an improved drinking water source. There are now only three countries (all located in sub-Saharan Africa and Oceania) with less than 50 per cent coverage, compared with 23 in 1990 [14]. New technologies for cheap water desalination and water collection from the air are also helping to improve the situation.
If population growth is not exactly an issue, then what is?
What we really should be concerned about is the age structure of the population. Regardless of the level of technological development, its core are the people of working age who are producing goods, paying taxes, and supporting the non-working groups, such as children and the elderly – the latter needing the most resources because of the state of their health.
Due to population aging, the share of working-age people is shrinking while the share of people who are at least 60 years old is growing. Population structure change is the most evident in Europe and Northern America, while the “Global South” has not experienced it yet – but will experience it in the next few decades.
Soon, one third of the population worldwide is going to be aged sixty or over, which means more social protection and healthcare expenditures and more working age people involved in nursing the elderly. However, it would be wrong and unjust to see the elderly as a burden, while these people have contributed so much to the incredible progress that our society has made.
They have all the same human rights as everyone, including the right to life and right to health. As age-related health deterioration is the main reason why society has to provide so much support to the elderly, it would be only logical to see the development of rejuvenation biotechnologies as the way to improve the situation.
What would life be like if we introduced rejuvenation technologies globally?
Before the era of universal medicine, people who managed to reach their sixties were still in relatively good health. However, once the onset of age-related diseases began, they died very quickly.
Modern medicine has changed that by slowing down the development of age-related diseases, hence extending the period of productivity. The downside is that this has also extended the period of illness, because treatments to prevent age-related diseases are not yet introduced into universal clinical practice.
In the near future, new interventions to slow down the aging process will become accessible, and then a shift will occur: the period of youth and adulthood will be extended due to better health, and the period of illness will be significantly postponed. In their sixties, people will remain as strong and vital as 40-year-old people are today. Some leading scientists predict that this may also lead to maximum lifespan increases of up to 150 years or more.
This is, of course, hard to prove, because as with many other things in human history, it is a unique situation that has never happened before, but some studies have proposed how aging would look given these three scenarios [15].
Fig 11. A:Pre Universal Medicine, B: Current medicine, C: Slowing aging. Source: Blagosklonny, M. V. (2012). How to save Medicare: the anti-aging remedy. Aging (Albany NY), 4(8), 547-52.
Whilst it is too early to be overly optimistic, we still should mention that apart from these three scenarios, there is a fourth possibility called negligible senescence. Negligible senescence in nature happens when a species does not display signs of aging, regardless of the passage of time. A number of species exhibit negligible senescence, including the rougheye rockfish (Sebastes aleutianus).
The ocean quahog (Arctica islandica) and some kinds of turtles are also negligibly senescent, but they still die because the expansion of their shell ultimately limits their movement. More examples can be found at the excellent HAGR (Human Ageing Genomic Resources) database.
At some point in time, medical technologies may become so sophisticated that they will be able to bring all of the processes of aging under medical control. If that is the case, then aging will always remain at a subclinical stage, because the repairs to our bodies will keep up the pace with damage accumulation, allowing people to look and feel young for an indefinite period of time.
Most likely, it will take decades for medical science to progress this far, but we should also admit that some of the technologies necessary for this transition already exist, e.g., stem cell therapies, early nanorobots, CRISPR and gene therapies, immunotherapies, senolytics, and geroprotectors (drugs that slow down the aging process).
How will increased lifespan affect population growth?
The possibility of significant life extension using medical interventions was not even considered by the academic community until recent years, so there were not many projections of how increased lifespans and negligible senescence would affect population growth. However, a few years ago, such a projection was done for Sweden.
One of the more realistic scenarios is one where only a small share of the population accepts negligible senescence technologies at the beginning (this could be due to a slow dissemination process, ethical or religious objections that people have to overcome, or a high cost of the new technology) with a gradual increase (1% added to the negligibly senescent group each year). It is assumed that some small share of the population will never accept these technologies and will age in the traditional way.
In this case, population change in Sweden will not lead to population growth but can, to some extent, mitigate the process of depopulation over 100 years of medical innovations [16].
Fig 12. Population projection for a scenario of growing acceptance of antiaging interventions. Projection of the Swedish population until year 2105, assuming the negligible senescence scenario for initially small proportion of population (10%), with growing acceptance rate over time. Life extension interventions start at age 60 years, with 30-year time delay from now.
This might be the likely scenario in most developed countries. Taking into account that new technologies tend to be expensive even for developed countries’ middle classes, the developing countries most possibly will reach the same level of implementation later in time, when their fertility rate will be already affected by the index of development. In this case, the fall of their population growth will be smaller due to decreased population mortality.
In a more optimistic scenario, where all the population has access to negligible senescence technologies and they are applied to everyone who is at least 60 years old, population growth in 70 years will be around 22%. The earlier the application, the bigger the population growth. If negligible senescence technologies are applied at the age of 40, then the estimated population growth will be nearly 47% in 70 years.
Fig 13. Projection of the Swedish population until the year 2105, assuming the negligible senescence scenario. Life extension interventions start at age 60 years, with a 30-year time delay from now.
There are three main conclusions we can make based on this data.
The growing share of people using negligible senescence technologies could help optimize the balance between workforce and retirees, hence maintaining economic development. People who are at least 65 years old will be about one-third of the global population in 2100, so we are talking about 3-4 billion old people who could be healthy and productive or ill and frail, depending on which strategy that global society implements.
Negligible senescence is a synonym of good health, which means that the burden of age-related diseases and their social consequences will be mostly eliminated.
Population growth, surprisingly, will not be as dramatic as is often imagined, leaving a significant period of time for adaptation, adequate measures of population growth control, and new territories’ development.
Is mitigating aging not only a need but also a legal obligation?
Even if negligible senescence remains a long-term goal, the emerging technologies to address the various aging processes [17] represent a unique opportunity to maintain older people in good health, allowing them to enjoy healthier lives, remain active, learn new skills, and contribute to the development of society. We owe them our present well-being. Not only have these people contributed a lot to create the things we have now, including better nutrition, healthcare, and a comfortable and safe habitat, they have also worked hard to change traditions and wisdom and helped to carry the concept of equal human rights forwards. This is why it is especially poignant to understand that geroprotective technologies and their potential are being underestimated and that they are not receiving the level of social approval and support that they rightly deserve.
According to the World Health Organization (WHO) Constitution, the objective of the WHO is “the attainment by all peoples of the highest possible level of health”. It is worth noting that WHO defines health as “a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity” [18]. While this definition may seem quite spacious, it was made this way purposefully to ensure that member states’ activities in improving the health of their people would never stop.
Conclusion
The need for constant improvement of health is now a universal consensus.
Aging represents the root cause of severe diseases, such as cancer, Alzheimer’s, stroke, Parkinson’s, heart disease, COPD, type 2 diabetes, osteoarthritis and atherosclerosis, leading to disability of the elderly and to a wide range of negative social consequences, which makes it the perfect target for the global healthcare system [19].
These diseases can only be cured if the actual aging processes are directly addressed and halted while the damage is repaired or reversed by medical interventions. Therefore, according to WHO and United Nations policy, this means that global society has an obligation to eventually cancel aging in order to achieve the highest possible level of health for all people.
Literature
United Nations, Department of Economic and Social Affairs, Population Division (2015). World Population Prospects: The 2015 Revision, Volume II: Demographic Profiles (ST/ESA/SER.A/380).
United Nations, Department of Economic and Social Affairs, Population Division (2015). World Population Prospects: The 2015 Revision, Data Booklet. ST/ESA/SER.A/377.
Mather, M. (2012). Fact sheet: The decline in US fertility. Population Reference Bureau, World Population Data Sheet.
Lanzieri, G. (2013). Towards a ‘baby recession’ in Europe?. Europe (in million), 16(16.655), 16-539.
Nargund, G. (2009). Declining birth rate in Developed Countries: A radical policy re-think is required. FV & V in ObGyn, 1, 191-3.
Camarota, S., & Ziegler, K. (2015). The Declining Fertility of Immigrants and Natives. Center for Immigration Studies.
UNITED NATIONS DEPARTMENT FOR ECONOMIC AND SOCIAL AFFAIRS. (2019). World Population Prospects 2019: Data Booklet. UN.
Myrskylä, M., Kohler, H. P., & Billari, F. C. (2009). Advances in development reverse fertility declines. Nature, 460(7256), 741-743.
United Nations, Department of Economic and Social Affairs, Population Division (1999). The World At Six Billion. ESA/P/WP.154.
Gráda, C. Ó. (2007). Making famine history. Journal of Economic Literature, 45(1), 5-38.
FAO, U., & Steinfeld, H. (2006). Livestock’s long shadow: Environmental issues and options. Rome:[sn].
Barbosa, G. L., Gadelha, F. D. A., Kublik, N., Proctor, A., Reichhelm, L., Weissinger, E., … & Halden, R. U. (2015). Comparison of land, water, and energy requirements of lettuce grown using hydroponic vs. conventional agricultural methods. International journal of environmental research and public health, 12(6), 6879-6891.
REN21. 2020. Renewables 2020 Global Status Report (Paris: REN21 Secretariat).
Unicef. (2015). Progress on Sanitation and Drinking-Water: 2015 Update and MDG Assessment. World Health Organization: Geneva, Switzerland.
Blagosklonny, M. V. (2012). How to save Medicare: the anti-aging remedy. Aging (Albany NY), 4(8), 547-52.
Gavrilov, L. A., & Gavrilova, N. S. (2010). Demographic consequences of defeating aging. Rejuvenation research, 13(2-3), 329-334.
López-Otín, Carlos et al.(2013). Hallmarks of Aging. Cell , Volume 153 , Issue 6 , 1194 – 1217
World Health Organization. (2014). Basic documents. World Health Organization.
Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., … & Rando, T. A. (2014). Aging: a common driver of chronic diseases and a target for novel interventions. Cell, 159(4), 709.
In a randomized, controlled human clinical trial, researchers have found that an eight-week program of diet, exercise, and meditation reduces epigenetic age by approximately two years in males between the ages of 50 and 72.
A prescription for health
For this study, the researchers used entirely conventional and widely recognized methods of improving health among elderly people.
The participants in the study group ate daily diets that were heavy in leafy greens, broccoli or other cruciferous vegetables, colorful vegetables, and beets, along with 6 ounces of animal protein, two servings of fruit, daily probiotic supplements, healthy oils, and methylation adaptogens such as green or oolong tea. Every week, three servings of liver and 5 to 10 eggs were included. Dairy, grains, legumes, and sugar were all excluded.
Weekday moderate exercise of 30 minutes was part of the treatment regimen, and the participants were required to get at least seven hours of sleep a night. Participants were instructed to perform Steps to Elicit the Relaxation Response, a specialized breathing regimen, at least twice a day.
Interestingly, the researchers refused to incorporate folic acid and B12 supplements into the participants’ diets, as these compounds had been previously shown to increase the risk of cancer [1].
Results
To measure epigenetic age, the researchers used the Horvath DNAmAge epigenetic clock. This clock is heavily correlated with chronological age, and it uses systemic and predictable biomarkers rather than random alterations to determine epigenetic age. The researchers considered this clock to be their best choice at the time the study was designed.
While the results were slightly mixed, and the majority of the participants showed no epigenetic benefit after being prescribed this regimen, methylation age was reduced by an average of nearly two years among the study group. Interestingly, non-participants were shown to have their methylation age increased by roughly one year over the course of the study, even though the study only lasted for eight weeks.
As to be expected from this kind of dietary and exercise regimen, group participants enjoyed reduced cholesterol from their values at the start of the study. Total cholesterol was decreased by an average of 22.8 mg/dL, and LDL cholesterol was decreased by an average of 16.8 mg/dL.
Emotional measurements were taken, but the results were not statistically significant.
Conclusion
As with most studies of this kind, this study could have strongly benefited from more participants, particularly since the results of the DNAmAge clock fluctuated so strongly: one member of the treatment group was aged by over eight years according to this clock, while another was youthened by nearly ten years. This may reflect basic inaccuracy or outside factors affecting the trial participants; human trials, particularly multi-factorial human trials, are susceptible to such confounding factors simply because trial participants do not live in the same controlled conditions as mice.
There is also no guarantee that the positive effects of these lifestyle interventions will last after they are ceased. It is unlikely that an eight-week regimen of any combination of diet, exercise, and meditation can permanently reduce epigenetic age. Rather, it is far more likely that these habits must be maintained in order to maintain their benefits.
Given the intensity of this intervention and the modest, limited results, readers may ask themselves whether engaging in this sort of dietary regimen is worth the time and trouble. While the results vary per person, and engaging in dietary overhauls or other significant changes in lifestyle should only be performed after a consulation with a qualified professional, the usefulness of these techniques has been made clear. It may be the case for some of our readers that practicing this sort of healthy lifestyle may allow them to live long enough for more effective interventions to be put into clinical practice, thus allowing them to live even longer.
We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
[1] Araghi, S. O., Kiefte-de Jong, J. C., Van Dijk, S. C., Swart, K. M., van Laarhoven, H. W., van Schoor, N. M., … & Van Der Velde, N. (2019). Folic acid and vitamin B12 supplementation and the risk of cancer: long-term follow-up of the B Vitamins for the Prevention of Osteoporotic Fractures (B-PROOF) Trial. Cancer Epidemiology and Prevention Biomarkers, 28(2), 275-282.
Date Posted: April 15, 2021
Comments Off on RNA Deep Sequencing Uncovers Parkinson’s Progression
A massive RNA sequencing effort has identified changes in microRNA associated with Parkinson’s. Some of the changes correlated with disease progression, holding out hope that they could be useful as prognostic or diagnostic biomarkers to help guide research and evaluate potential therapies.
Pinning down Parkinson’s
Although Parkinson’s disease is the second most common neurodegenerative disease globally, researchers lack some of the key tools to understand and address the condition. Parkinson’s varies extensively in its pathophysiology and clinical features, making it hard to evaluate therapeutic outcomes in clinical trials. Disease progression can also vary considerably, and the interplay of genetic and environmental factors driving this remains poorly understood. The inability to properly track Parkinson’s has hampered the development of an effective therapy.
Biomarkers could alleviate this problem. Sufficiently reliable, precise biomarkers would make it possible for researchers to select a homogeneous population for a study. They would also provide objective endpoints against which to evaluate therapeutic interventions as well as a way to measure disease progression.
MicroRNAs are a promising pool of candidate biomarkers for conditions like Parkinson’s. These are a class of small, noncoding RNAs that influence gene activity by regulating messenger RNAs transcribed from genes. While high-throughput sequencing has led to genomic and transcriptomic investigations of Parkinson’s, to date, there has been less research on the role of small noncoding RNAs such as microRNAs.
Large cohort, deep sequencing
This new study describes how an international team has used RNA sequencing of samples from a large cohort to identify microRNAs that could serve as Parkinson’s biomarkers. They were able to draw on the Parkinson’s Progression Markers Initiative (PPMI), a public-private partnership launch by the Michael J Fox Foundation in 2010 with the goal of identifying specific progression markers for Parkinson’s. PPMI includes participants at clinical sites spread across 11 countries. Together comprehensive clinical phenotyping coupled with outpatient follow-up of more than 10 years, this makes it an extremely valuable resource for understanding and investigating the variability and progression of Parkinson’s.
The team analyzed RNA sequences from thousands of patients with different types of Parkinson’s. They included the initial samples as well as follow-up time points so they could study disease progression. While their sequencing uncovered many kinds of small noncoding RNAs, they chose to focus the analysis on microRNAs. They also verified their findings with data from an independent cohort.
The analysis uncovered a set of microRNAs that are dysregulated in Parkinson’s patients. The dysregulation occurred in two waves, one in patients in their 30s and another in their 70s. This is extremely useful, since it bolsters the idea that the molecular underpinnings of early-onset and late Parkinson’s are different. With the identity of some of the molecular actors in hand, researchers can try to tease apart the different etiologies.
The team also identified changes in microRNA that correlated with disease progression, differing between patients in whom the disease progressed quickly and those in whom it remained relatively stable. They were also able to distinguish between different types of Parkinson’s disease.
Finally, the researchers mapped these microRNA changes to networks of messenger RNA in order to get an idea of the resulting changes in gene activity and discover which processes were affected. For example, they report that mitochondrial dysfunction seems to be important, though it remains unclear whether this is a causeudisluteo or consequence of the disease, and their findings also implicate changes in the inflammatory response.
Noncoding RNAs have diagnostic and prognostic importance in Parkinson’s disease (PD). We studied circulating small noncoding RNAs (sncRNAs) in two large-scale longitudinal PD cohorts (Parkinson’s Progression Markers Initiative (PPMI) and Luxembourg Parkinson’s Study (NCER-PD)) and modeled their impact on the transcriptome. Sequencing of sncRNAs in 5,450 blood samples of 1,614 individuals in PPMI yielded 323 billion reads, most of which mapped to microRNAs but covered also other RNA classes such as piwi-interacting RNAs, ribosomal RNAs and small nucleolar RNAs. Dysregulated microRNAs associated with disease and disease progression occur in two distinct waves in the third and seventh decade of life. Originating predominantly from immune cells, they resemble a systemic inflammation response and mitochondrial dysfunction, two hallmarks of PD. Profiling 1,553 samples from 1,024 individuals in the NCER-PD cohort validated biomarkers and main findings by an independent technology. Finally, network analysis of sncRNA and transcriptome sequencing from PPMI identified regulatory modules emerging in patients with progressing PD.
Conclusion
Taken as a whole, this study provides a systemic overview of the changes in microRNA in different types of Parkinson’s and at different time points. This molecular data will be an invaluable resource in guiding future research on the disease, whether to understand its biology or to develop potential therapies. While further research will be needed to determine if the microRNA changes meet the criteria to be used a biomarkers – for example, determining their specificity to Parkinson’s – this work is a first step in that direction.
We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
When conducting science, it is crucially important to have clear, unambiguous definitions. These definitions must be firmly established to avoid confusion and misunderstandings and possibly to prevent people from going around telling everyone that you’re working on something that you’re actually not.
The I-word
It’s not uncommon, especially for outsiders of a given field, to use an inappropriate word to indicate a more complex concept than the word itself conveys—maybe because they think that the two are close enough or possibly because they just don’t see the difference.
For this reason, it’s likely that each field has its own unspeakably profane word; in the field of rejuvenation biotechnology, that word is the dreaded I-word: immortality.
Before I explain why it is a dreaded word, it’s important to define what the heck it even means. Now, of course definitions are entirely arbitrary, and the same word could mean a different thing to a different person; but if we go with the most intuitive, commonly accepted meaning of “immortality” when nothing else is specified, then we can safely say it describes the quality of someone who cannot die. In other words, it refers to an immortal being could not be killed or die in any way, even if it wanted to.
Just like people today who would like to live for an indefinitely long time (like me) are forced to eventually die by aging and are thus stuck without a choice (at least until we figure rejuvenation out), a hypothetical immortal being would be in a similar situation, with no choice to terminate its life because its immortality would force it to live forever. This brief articleexplains the issue very nicely and concisely.
Now, the way I approach life, immortality wouldn’t be all that bad, because I am skeptical that I’d ever have a reason to want to die. Still, I appreciate that I might be wrong, so if I could choose and wanted to play it really safe, I’d opt for an “immortality switch”; as long as it is on, you’re immortal; if and when you get tired of life, you flip it off and you become mortal again, free to get rid of your own life however you see fit.
Unfortunately, an immortality switch is just about as improbable as immortality itself. Think about it: to be immortal, your chance of ever dying of any cause at all should be exactly zero. There’d be no gun, no disease, no poison, no amount of air taken out of your lungs, no stellar explosion capable of terminating your existence. The inner workings—biological or not—keeping you alive should be indestructible, able to withstand forces of any magnitude and keep going under any possible circumstance (including running out of energy).
Even without dragging the fabled heat death of the universe into the mix, it’s difficult to imagine how any of this could ever be possible—let alone a switch turning this unlikely ability on and off.
What’s the difference?
I’m not going to go as far as to say that the above is completely impossible; I was trained to make such bold claims only when I can prove them, so I’ll just say that, to the best of my knowledge, this sort of immortality appears to be exceedingly unlikely.
Now, whether immortality is possible or not is an intriguing question, but it is decidedly off-topic in the field of rejuvenation, because rejuvenation is not immortality. If a universal antiviral drug able to wipe the floor with every conceivable virusexisted, you wouldn’t call it an immortality drug, because right after leaving the doctor’s office where you got your miracle shot, a grand piano might happen to crush you after a 50-story free fall, and the antiviral drug wouldn’t be especially effective against that particular cause of death. Similarly, rejuvenation would save you from death by age-related diseases, but not by falling grand pianos, sadly.
Yet, both people and the media keep talking about “curing death” and “immortality pills” when the actual topic is rejuvenation biotechnology; this is a cause of particular annoyance to Dr. Aubrey de Grey, whose pioneering work on aging is constantly called an “immortality quest” and similar things. Dr. Aubrey de Grey remarked during an interview at Vice “Don’t use the word immortality when you talk about my work. It’s taken; it’s a religious word”. Some may consider the indefinite lifespans that Dr. Aubrey de Grey has suggested may be possible through the medical control of aging as the same as immortality, but it is not, as we discuss here.
Don’t use the word immortality when you talk about my work. It’s taken; it’s a religious word – Dr. Aubrey de Grey
Since immortality reasonably seems a pipe dream and is laden with all sorts of ethical issues and concerns, whether justified or not, this results in a gross misrepresentation of the entire field and a lot of unwarranted bashing of completely legitimate medical research whose only fault is that it aims to prevent the diseases of aging rather than just coping with them.
The same story is true of negligible senescence. If a successful rejuvenation platform were implemented, people would still age biologically, but we would have therapies capable of undoing such aging. Through periodic reapplication of these therapies, the hallmarks of agingwould always be kept well below the pathology threshold. In other words, we would still senesce (that is, age), but our level of senescence would stay negligible—that’s where the term comes from.
Yet, many people keep calling negligible senescence immortality, just like they do rejuvenation biotechnology, whether deliberately or by genuine mistake, thereby providing an excellent strawman for needy critics to beat. And this is the reason why the I-word is dreaded in this field, by the way.
Negligible senescence is the expected result of truly comprehensive rejuvenation biotechnologies, and yes, if we got there, our healthspan would be vastly increased, and consequently, so would our lifespan; if you were in perfect health for longer than, say, 100 years, it is a disarmingly trivial consequence that you would live for longer than 100 years.
However, whether a negligibly senescent person then lives on forever or not, or ten thousand years from now, someone beats the odds and comes up with a fancy immortality switch, is an entirely different matter that is beyond the scope of the field of rejuvenation biotechnology. Speaking of which, let me reiterate once more what its actual scope is: to eradicate age-related diseases. All the rest, whether consequential effects or downright made-up rubbish, is just unnecessary embroidery.
Astoundingly, this means that a population explosion has passed relatively unnoticed – all thanks to the “Green Revolution” (rapid development of new agriculture techniques, such as fertilizers, irrigation and selection). The concern that there will be a food shortage in the future neglects further technological advances such as aquaponics, hydroponics, aeroponics, vertical farming, 3D-printed housing, algae farms, and many other technologies that could provide enough food for all.
New technologies can provide solutions for the numerous environmental issues related to traditional farming. For instance, hydroponics offers around 11 times higher yields while requiring 10 times less water than conventional agriculture [12]. The energy needs of a hydroponic facility are much higher (up to 80 times more), but thanks to emerging 
There are attempts to create new edible products that taste like meat but are completely without animal ingredients, such as 
