The Blog

Building a Future Free of Age-Related Disease

Some People think Life Extension is “Just a Fear of Death”

Sometimes those working in the field of rejuvenation biotechnology face the accusation that what they are doing is just a fear of death, like not being scared of age-related diseases is somehow brave.

War used to be fashionable but now it isn’t

These days, war is not really portrayed in a very good light. When we think about war, we think about genocide, mass murder, and slaughter, and we call for an end to it. The popular sentiment is that war is bad and we should just do away with it.

However, once upon a time, things were rather different, and soldiers fighting wars were not seen as victims of mindless violence. Losing your life in battle was considered glorious and noble, and your family would be proud of you for fighting in the name of your country, your God, or whatever. People who were afraid of dying and refused to fight were regarded as cowards, most certainly not as pacifists of a strong moral fiber, and were possibly shunned, punished, or even executed; being a conscientious objector was not yet a thing, and human rights weren’t either.

This is sheer madness to us, but back in the day, it was entirely normal. Most of us will probably think people must have been crazy to let themselves be fooled into believing such nonsense, but that’s the power of propaganda for you.

The modern age of pro-death propaganda

However, the story is not completely over even today. This may be because of past glorification of death, stale ideas about the “circle of life”, a widespread coping mechanism, or a combination of the three, but at least in certain circumstances, being afraid of death is still seen as a sign of cowardice and sometimes also inferiority.

In particular, advocates of healthy life extension are sometimes accused of being “just afraid of death.” That’s quite an odd phrasing, as the word “just” is rather trivializing. Fear is nothing but a biological mechanism that pushes individuals to avoid danger, and this mechanism has evolved because individuals without it did not survive. In particular, fear of death is what has pushed a significant portion of all life forms to go through the trouble of avoiding extinction, so it has always been one of the most crucial parts of our existence. Besides, death is the end of everything we are and love, so it’s actually a rather big deal, and the fear of it is an absolutely legitimate one and not to be trivialized.

Of course, fear of death, or more generally of danger, can sometimes get in the way of things. In particular, it gets in the way of rulers who want to conquer another country and need soldiers to do so, which is why losing your life in battle was glorified in the past—it was an incentive, though by no means the only one, to persuade people to put themselves at risk for someone else’s interest. As said, this continues today in a different form, with some people advocating for the alleged necessity of death for more selfless reasons—the good of the environment, the species, society, or what have you.

We have discussed these other reasons in a number of other articles; the point here is that not all death is seen as necessary for their fulfilment, but generally only age-related death, which, much like war-related death in the past, is considered a “just” death, and this is because of a misconception that I discussed here. It would appear that acceptable kinds of death are decreasing in number over time, age-related death being one of the few ones still standing.

Think of it as “life preservation”

“Life extension” is an unfortunate choice of words, because it conveys two wrong ideas. The first is that there is some kind of predetermined life duration beyond which we want to extend our lives. This is most definitely not the case, as an organism’s lifespan is not set in stone and is largely influenced by external factors. Even the limits deriving from genetic makeup are not ironclad and can be manipulated, at least in certain species.

The second is that “extension” might feel as some sort of undue appropriation of what is not yours, an attempt to get more than your fair share allotted by nature. This is also not the case, because at no point did nature sit down to decide what was due and what was undue; these are human concepts that are entirely extraneous to nature, which is not in the habit of deciding anything, let alone what is or isn’t fair.

A better choice of words would be “life preservation,” because the whole point of medicine is that of preserving our lives for as long as possible, not simply reducing suffering. If that were the case, rather than battling with cancer, doctors would just inject oncological patients with lethal doses of morphine. However, “life preservation” is pretty much taken by the environmental sciences and could, therefore, be misleading, so “life extension” it is. However, it ought to be defined as the act of preserving healthy lifespan for as long as possible, including beyond traditional limits.

Therefore, life extension can include things that you would hardly consider as life extension technologies. LEAF board member Paul Spiegel was correct when he said that “a toothbrush is life extension technology.” It’s an everyday item, hardly impressive by modern standards, but it helps you keep your teeth for longer and maintain oral hygiene, thereby allowing you to feed yourself more easily than if you didn’t have teeth and prevent infections that might shorten your days.

A motorcyclist’s helmet is a life extension technology in that it may allow you to extend your life past the point when you’re hit by a careless driver while riding your bike. Normally, we think motorcyclists who wear helmets are wise; no one walks up to them and says, “Oh, you’re just afraid of death.” (Try saying that somebody brushing his or her teeth—I bet you’ll get the blankest stare of your life.) Granted, none of these things will allow you to extend your life past the grip of age-related diseases, but that’s just because they’re not the right technology for the job. A helmet extends your life by preventing only a certain kind of death, and so does rejuvenation biotechnology, except the kind of death involved is different.

Is life extension just a fear of death?

Some life extension supporters are afraid of death, and I know I certainly am. Don’t get the wrong idea; this doesn’t mean that I constantly panic about how I might die, as that would be useless and counter-productive. Being afraid of death, or more generally of anything, simply means having a sense of the danger it presents and taking action to prevent that danger.

In a similar way, a motorcyclist who wears a helmet during a ride is taking action to prevent injury and death, and this only means that he or she is being cautious, not panicking all the time. Unfortunately, the equivalent of a helmet for life extension supporters, rejuvenation biotechnology, does not yet exist, so before we can wear it, we need to push for it to be created.

There is an old saying that only fools know no fear, and this is definitely true in the case of fear of death. Fear of death is what makes us call for bans on nuclear weapons and makes us feel uneasy when world leaders threaten military action. It’s a reminder that we value our lives and that we should protect them, not letting anything or anyone impair their quality or terminate them. Hardly anyone these days would say that refusing war, or taking a malaria shot, mean that one’s “just afraid of death” in a derogatory way.

Dying in combat or by an infectious disease is considered a “premature” death, and as such, everyone understands why that sort of death is feared. However, that of “premature death” is a rather bizarre concept; it implies that there is a point when death is timely, although even its advocates don’t seem to have reached a consensus as to when exactly this point is and how death should then occur.

I hold that all deaths are premature and untimely, the only exception being when one actually wants it for him or herself, and they all should be feared in the sense of perceiving the danger and taking action to avoid it. The goal of life extension is, of course, to avoid disease along with death, for there would be no point in living a really long time if most of it was spent being sick and suffering.

Not all life extension supporters may be afraid of death, but for the reasons above, they probably should be, and they should be afraid of disease as well. Claiming not to fear death, or worse, anything at all, is more often than not just a way to flaunt one’s own ego, but there is little use for that once disease or death have struck.

Neurons

Gene Therapy Improves the Brains of Mice With Alzheimer’s

Scientists have successfully improved learning and memory, as well as neuronal morphology, in Alzheimer’s-prone mice with the help of a gene therapy that upregulates a vital protein [1].

Alzheimer’s disease (AD) has been a notoriously hard problem to crack, despite major R&D investment. AD has long been associated with the accumulation of amyloid-beta (Aß) plaques and tau-protein tangles in the brain, and most previous efforts were directed at removing those. This approach, unfortunately, resulted in some spectacular flops. Although research in this direction continues, scientists worldwide have been actively searching for alternative approaches. One of them postulates that even if we do not know how exactly AD causes our brain to falter, we could try to counter its effects by boosting the brain’s ability to function.

Cellular “life rafts”

Cellular membranes were thought to be homogenous, but a consensus is growing that membranes consist of various structurally different regions, such as membrane/lipid rafts (MLRs). MLRs are characterized by a high concentration of certain molecules, including cholesterol. This results in structural differences, compared to the surrounding membrane, that make MLRs appropriate for cellular signaling [2], which occurs when molecules from outside the cell attach themselves to receptors on the cell’s membrane and influence its behavior via complex chemical pathways. MLRs support these vital interactions through their unique structural properties.

In neurons, MLRs host most of the neurotrophin receptors. Neurotrophins, such as nerve growth factor (NGF), are a group of proteins indispensable for neuronal function [3]. AD patients are known to exhibit impaired neurotrophic signaling, especially in the cortex and the hippocampus [4]. This neurotrophin deficiency is thought to affect neuroplasticity – the natural ability of neurons to adapt to the changing environment.

Reinforcing cellular scaffolds

Caveolin-1 is a scaffolding protein, meaning that it helps maintain cellular structure – specifically, in MLRs – by binding other proteins together. Decreased expression of the Cav-1 gene is associated with learning and memory deficits in transgenic AD mice. Having chosen caveolin-1 as their target, the researchers attempted to upregulate it in hippocampal neurons using viral vectors.

Gene therapy with viral vectors is a rapidly developing and highly promising field, and several COVID-19 vaccines are built this way. The researchers used AAV (adeno-associated virus), a popular source for viral vectors that are thought to be completely harmless to humans [5]. Before the viral capsids are injected into the body, most of the viral genome gets replaced with other sequences, and this recombinant genome does not do much except for coding for the desired protein (caveolin-1, in this case). Contrary to wild AAVs, the recombinant virus does not have the ability to integrate itself into the human genome. Instead, its DNA forms circular plasmid-like fragments that reside in the nucleus. They persistently produce the protein and can even survive cellular division.

The caveolin-encoding gene was designed to be expressed only in the presence of synapsin – a protein that is present mostly, or exclusively, in neurons. This clever technique helps restrict protein production to a specific cell type.

Not just AD

Having selected their study and control groups, the researchers injected the viral vectors into the hippocampi of three-month-old mice. While the treatment began quite early in life, high levels of caveolin in the aged mice prove that the recombinant DNA continued to work during the whole lifespan. Thus, virus-based gene therapy can produce lasting effects even after a single treatment.

The tests were conducted at the ages of 9 and 11 months, when transgenic mice of this type already exhibit AD-like symptoms. The researchers showed that the treatment was able to significantly rescue learning and memory abilities that were impaired in the controls. On top of that, the treatment preserved MRLs morphology and several markers of normal neuronal function, such as synaptic structure and dendritic density. Interestingly, these beneficial outcomes were not due to reduced Aß and tau levels. As the researchers note, this means that the method they have developed may produce even better results in combination with treatments that target Aß and tau pathologies. Another takeaway is that caveolin therapy can probably be used to treat not just AD but also other forms of neurodegeneration of different or unknown etiology.

Conclusion

Although mouse AD models do not fully mimic human AD, as evidenced by the failure of multiple human trials after promising mouse trials, this study might be different, since it targets basic aspects of neuronal function and survivability. Gene therapy with viral vectors holds great promise, and every new success adds to our understanding of its immense potential – after all, downregulation of important genes is responsible for many diseases, including age-related ones. It seems that very soon, medicine will be able to complement natural protein production as it falters with age.

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.

Literature

[1] Wang, S., Leem, J. S., Podvin, S., Hook, V., Kleschevnikov, N., Savchenko, P., … & Head, B. P. (2021). Synapsin-caveolin-1 gene therapy preserves neuronal and synaptic morphology and prevents neurodegeneration in a mouse model of AD. Molecular Therapy-Methods & Clinical Development, 21, 434-450.

[2] Alves, A., Dias, R. A., Kagami, L. P., das Neves, G. M., Torres, F. C., Eifler-Lima, V. L., … & Kawano, D. F. (2018). Beyond the. Current medicinal chemistry, 25(18), 2082-2104.

[3] Huang, E. J., & Reichardt, L. F. (2001). Neurotrophins: roles in neuronal development and function. Annual review of neuroscience, 24(1), 677-736.

[4] Yuan, D., Zeng, C., Chen, Q., Wang, F., Yuan, L., Zhu, Y., … & Chen, N. (2017). Root-Securing and Brain-Fortifying Liquid Upregulates Caveolin-1 in Cell Model with Alzheimer’s Disease through Inhibiting Tau Phosphorylation. Neurology research international, 2017.

[5] Wang, D., Tai, P. W., & Gao, G. (2019). Adeno-associated virus vector as a platform for gene therapy delivery. Nature reviews Drug discovery, 18(5), 358-378.

Dividing cells

Harnessing the Unaging Germline

A team of researchers, including Michael West of AgeX Therapeutics, has authored a review paper that posits a fundamental difference between “immortal” germline cells and “mortal” somatic cells.

The two types of cells

This review paper, which cites 175 other papers, goes back throughout history, discussing the very earliest scientific theories of aging. It talks about the concept of antagonistic pleiotropy, which is the idea that aging and its accompanying diseases are the result of evolutionary adaptations that favor young organisms’ ability to reproduce, regardless of how those adaptations harm them later in life, It also describes the “wear and tear” damage accumulation theory of aging, which was famously popularized by Dr. Aubrey de Grey and the SENS Research Foundation.

This paper acknowledges the effects of both antagonistic pleiotropy and damage accumulation in aging organisms. However, it also notes that the cellular germline is fundamentally immune to both of these effects. As supporting evidence, it describes organisms that do not exhibit senescence as well as the germline of all organisms, which it describes as “uncoupled from time”.

With this framework in mind, the ultimate goal of aging research is to bring the clock-uncoupled nature of germline cells to stem cells and somatic cells, thus resetting an organism’s age.

The Hayflick limit

As part of its historical journey, this paper describes the Hayflick limit, which is often (incorrectly) cited by opponents of aging research as a hard reason why most multicellular organisms cannot live indefinitely. We now know that the Hayflick limit is a downstream consequence of telomere attrition, which is listed in the Hallmarks of Aging as a primary hallmark.

This paper points out that telomere attrition, which it describes as a telomere clock, only occurs in somatic cells, not in germline or pluripotent cells. This paper points out that telomere attrition is a cause of cellular senescence, a downstream hallmark of aging [1]. It highlights telomeres as one of the most fundamental differences between pluripotent cells and somatic cells.

Epigenetic alterations

Epigenetic alterations are also a primary hallmark of aging, and this paper points out that, while the epigenetics of germline cells do, in fact, change with age, they are reset upon fertilization [2]. This paper covers ground that we have frequently discussed on lifespan.io, most notably the multi-tissue Horvath epigenetic clock, which has a median accuracy of under four years [3].

This review cites a paper, of which Dr. Horvath is also an author, showing that despite being in different states of differentiation, cells in the retina share the same epigenetic age [4]. Therefore, epigenetic age, unlike telomeres, is maintained across the organism; your somatic cells and stem cells are the same age according to this clock. On the other hand, if you receive a stem cell transplant from a young person, those cells and their daughter somatic cells are, epigenetically, the same age as their donor [5].

This review cites many instances of accelerated and decelerated epigenetic aging. People who are long-lived, unsurprisingly, enjoy a reduced epigenetic age compared to their chronological age [6], and, as we have pointed out before, lifestyle interventions have positive effects on epigenetic aging.

Transposable elements

The final clock discussed by this paper involves transposable elements, which are repetitive elements in the genome. Their location and prevalence represent genomic instability, another hallmark of aging. While they comprise 40% of the mammalian genome and are the result of endogenous retroviruses [7], most of these elements are inactive. The paper explains that their activation is often caused by double-strand breaks, a key element of genomic instability [8].

The paper also suggests a possible mechanism by which the germline is protected against this form of genomic instability. It mentions two types of non-coding RNA, including the PIWI-piRNA pathway, which may allow for the silencing of transposable elements and thus the indefinite proliferation of germ-line cells [9]. This pathway is found in non-senescent animals, such as the hydra, a marine creature that does not exhibit aging, and evidence has been uncovered linking this pathway to its supposedly indefinite lifespan [10].

The nature of the soma

The paper caps off its discussion of clocks and somatic cells by pointing out related facts about aging, such as its beginning at the embryonic stage of life. In fact, we lose half our telomere length before we are even born, and this rapid decine continues until the age of three [11]. Unsurprisingly, mammalian aging is highly variable; despite our close relation to chimpanzees, we live roughly four times as long as they do, and the naked mole rat exhibits negligible senescence [12]. Therefore, it is not unreasonable to believe that other species of mammals, such as human beings, may obtain the same ability.

Abstract

Multicellular life evolved from simple unicellular organisms that could replicate indefinitely, being essentially ageless. At this point, life split into two fundamentally different cell types: the immortal germline representing an unbroken lineage of cell division with no intrinsic endpoint and the mortal soma, which ages and dies. In this review, we describe the germline as clock-free and the soma as clock-bound and discuss aging with respect to three DNA-based cellular clocks (telomeric, DNA methylation, and transposable element). The ticking of these clocks corresponds to the stepwise progressive limitation of growth and regeneration of somatic cells that we term somatic restriction. Somatic restriction acts in opposition to strategies that ensure continued germline replication and regeneration. We thus consider the plasticity of aging as a process not fixed to the pace of chronological time but one that can speed up or slow down depending on the rate of intrinsic cellular clocks. We further describe how germline factor reprogramming might be used to slow the rate of aging and potentially reverse it by causing the clocks to tick backward. Therefore, reprogramming may eventually lead to therapeutic strategies to treat degenerative diseases by altering aging itself, the one condition common to us all.

Conclusion

As the researchers point out, the goal of aging research is to uncouple biological age from chronological age. The OSKM epigenetic reset is touted as a potential method for rejuvenating cells, and the paper goes into deep detail about how epigenetics may be restored back to a youthful state in living organisms as well as the health and social benefits for doing so. If we can harness these resetting abilities, which naturally occur in the germ line and in many other organisms, we can cross out epigenetic alterations, telomere attrition, and some aspects of genomic instability from our to-do list regarding the root causes of aging.

Literature

[1] Tchkonia, T., Zhu, Y., Van Deursen, J., Campisi, J., & Kirkland, J. L. (2013). Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. The Journal of clinical investigation, 123(3), 966-972.

[2] Zeng, Y., & Chen, T. (2019). DNA methylation reprogramming during mammalian development. Genes, 10(4), 257.

[3] Horvath, S. (2013). DNA methylation age of human tissues and cell types. Genome biology, 14(10), 1-20.

[4] Hoshino, A., Horvath, S., Sridhar, A., Chitsazan, A., & Reh, T. A. (2019). Synchrony and asynchrony between an epigenetic clock and developmental timing. Scientific reports, 9(1), 1-12.

[5] Søraas, A., Matsuyama, M., de Lima, M., Wald, D., Buechner, J., Gedde-Dahl, T., … & Matsuyama, S. (2019). Epigenetic age is a cell-intrinsic property in transplanted human hematopoietic cells. Aging Cell, 18(2), e12897.

[6] Gutman, D., Rivkin, E., Fadida, A., Sharvit, L., Hermush, V., Rubin, E., … & Atzmon, G. (2020). Exceptionally long-lived individuals (ELLI) demonstrate slower aging rate calculated by DNA methylation clocks as possible modulators for healthy longevity. International journal of molecular sciences, 21(2), 615.

[7] Cordaux, R., & Batzer, M. A. (2009). The impact of retrotransposons on human genome evolution. Nature Reviews Genetics, 10(10), 691-703.

[8] White, R. R., & Vijg, J. (2016). Do DNA double-strand breaks drive aging?. Molecular cell, 63(5), 729-738.

[9] Sturm, Á., Perczel, A., Ivics, Z., & Vellai, T. (2017). The Piwi-pi RNA pathway: road to immortality. Aging cell, 16(5), 906-911.

[10] Teefy, B. B., Siebert, S., Cazet, J. F., Lin, H., & Juliano, C. E. (2020). PIWI–piRNA pathway-mediated transposable element repression in Hydra somatic stem cells. RNA, 26(5), 550-563.

[11] Sidorov, I., Kimura, M., Yashin, A., & Aviv, A. (2009). Leukocyte telomere dynamics and human hematopoietic stem cell kinetics during somatic growth. Experimental hematology, 37(4), 514-524.

[12] Buffenstein, R. (2008). Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species. Journal of Comparative Physiology B, 178(4), 439-445.

Journal Club

Aging Begins After a Rejuvenation Event in Early Life

The Journal Club hosted by Dr. Oliver Medvedik returns for another episode on May 25th at noon Eastern / 5 UK time live on our Facebook page. This month, we have one of the authors, Dr. Vadim Gladyshev, joining us, and he will be talking us through this new research. Vadim and his team report that they have discovered that aging does not begin as early as we thought in humans but follows a “rejuvenation event” during embryogenesis that truly signals the start of aging.

It should be noted at this point that the study in question is currently in pre-print over at bioRxiv, and so the data has not been peer reviewed. It should not be regarded as conclusive, nor should it guide clinical practice or health-related behavior.

The notion that germline cells do not age goes back to the 19th century ideas of August Weismann. However, being in a metabolically active state, they accumulate damage and other age-related changes over time, i.e., they age. For new life to begin in the same young state, they must be rejuvenated in the offspring. Here, we developed a new multi-tissue epigenetic clock and applied it, together with other aging clocks, to track changes in biological age during mouse and human prenatal development. This analysis revealed a significant decrease in biological age, i.e. rejuvenation, during early stages of embryogenesis, followed by an increase in later stages. We further found that pluripotent stem cells do not age even after extensive passaging and that the examined epigenetic age dynamics is conserved across species. Overall, this study uncovers a natural rejuvenation event during embryogenesis and suggests that the minimal biological age (the ground zero) marks the beginning of organismal aging.

If you are a Lifespan Hero, you can join us live on the call; just visit the Heroes Corner for connection details, or look out for an email from us soon.

Literature

Kerepesi, C., Zhang, B., Lee, S. G., Trapp, A., & Gladyshev, V. N. (2021). Epigenetic clocks reveal a rejuvenation event during embryogenesis followed by aging. bioRxiv.

Centenarian

People Living 105+ Years Appear to Repair DNA Better

A new study has shown that people who live for over 105 years typically have a genetic makeup that allows better repair of DNA damage [1].

Looking at the genomes of people who enjoy extreme longevity

There has always been lots of interest in what allows some people to live considerably longer than their peers, but it has never been clear how they do it. The new study is the first to take a really detailed look at the genomes of these super-agers and why they might enjoy increased longevity. Not only do such people live a lot longer, the additional time is often spent in good health and without age-related diseases.

The researchers studied the genomes of 81 people aged 105 or older and compared them with 36 healthy people from the same area of Italy with an average age of 68. Taking blood samples, they then conducted whole-genome sequencing, looking for differences in genes between the two groups.

They noticed that there were a total of five common genetic alterations to the genes COA1 and STK17A that were prevalent in the 105+ group. To confirm this, they cross-checked these findings against other published studies and saw the same gene variants in people 100 years and older.

Alterations increasing the activity of the STK17A gene were commonly seen in people living to 105+ years. STK17A plays a role in the cellular response to DNA damage, pushing damaged cells to destroy themselves in a process called apoptosis and regulating the levels of reactive oxygen species present in cells. These things are important for healthy cell function and retiring damaged cells from circulation in order to reduce the risk of cancer and other diseases.

Alterations of the COA1 gene that resulted in reduced expression of the gene were also commonly observed in people living 105+ years. This particular gene is a mediator of communication between the cell nucleus and mitochondria.

Finally, the same area of the genome is associated with increased expression of the BLVRA gene in some tissue types. This particular gene is associated with the removal of reactive oxygen species from cells. These can damage parts of the cell, including the mitochondrial genome, if present in excessive amounts. They are often excessively produced by the mitochondria within aged cells. Old mitochondria are no longer efficient at producing energy and increasingly produce excessive reactive oxygen species as a byproduct.

Repairing DNA is a key to extreme longevity

Efficient DNA repair is typically a common feature of long-lived species; for example, the naked mole rat can live thirty years or longer and has very efficient DNA repair. This is a huge difference when compared to other rodents, which generally live between 1 to 3 years.

The researchers suggest that this is also true in humans and that people living to 105 and beyond have genomes that are better able to repair DNA damage. That DNA repair is an important determinant of lifespan is probably no surprise, given that DNA damage is believed to be one of the nine reasons we age.

In further support of this, the team also looked at the occurrence of DNA mutations in the genomes of each group of participants. Mutations can happen naturally and accumulate as we age. They discovered that people aged 105+ had a lower incidence of mutations in six out of seven genes that they examined. These long-lived individuals are more resilient to mutations, which may be another contributing factor for their longevity and reduction of age-related disease incidence.

The researchers conclude that their results suggest that efficient DNA repair and low mutational burden during life are two key reasons that some people enjoy increased longevity and health.

Abstract

Extreme longevity is the paradigm of healthy aging as individuals who reached the extreme decades of human life avoided or largely postponed all major age-related diseases. In this study, we sequenced at high coverage (90X) the whole genome of 81 semi-supercentenarians and supercentenarians [105+/110+] (mean age: 106.6 ± 1.6) and of 36 healthy unrelated geographically matched controls (mean age 68.0 ± 5.9) recruited in Italy. The results showed that 105+/110+ are characterized by a peculiar genetic background associated with efficient DNA repair mechanisms, as evidenced by both germline data (common and rare variants) and somatic mutations patterns (lower mutation load if compared to younger healthy controls). Results were replicated in a second independent cohort of 333 Italian centenarians and 358 geographically matched controls. The genetics of 105+/110+ identified DNA repair and clonal haematopoiesis as crucial players for healthy aging and for the protection from cardiovascular events.

Conclusion

While the debate over the importance of genomic instability continues in academic circles, this study lends support to the idea that maintaining a stable genome, and being better able to repair damage to it, is a key factor in longevity. Knowing the associated genes and their variants also opens the door for future gene therapies that equip everyone with the same gene variants, thus granting them increased healthy longevity 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.

Literature

[1] Garagnani, P., Marquis, J., Delledonne, M., Pirazzini, C., Marasco, E., Kwiatkowska, K. M., … & Franceschi, C. (2021). Whole-genome sequencing analysis of semi-supercentenarians. Elife10, e57849.
Bigmouth Buffalo Fish

No Sign of Aging in Long-Lived Bigmouth Buffalo Fish

Extremely long-lived bigmouth buffalo fish show no signs of a physiological decline with age, according to a new study. This clear example of negligible senescence in aging vertebrates demonstrates the need to better understand the mechanisms underlying senescence and points the way towards research that could clarify them.

Variable senescence

Senescence consists of various changes in physiology, such as altered stress response and decreased immune function. Although there is variation in how quickly senescence occurs, it has been found to increase with age along with other age-related changes such as the shortening of telomeres. However, the existence of variability in senescence rates shows that the mechanisms underlying senescence are at least partially explicable by different life histories.

Differences in the pace of senescence change how age affects an organism. For example, naked mole rats remain fertile even at an advanced age, which is a consequence of the evolutionary dynamics that shaped this species’ life history. Understanding the factors that shape the mechanisms behind senescence is an important step towards learning to modulate them – in other words, learning how to live longer without getting old.

A team of researchers used bigmouth buffalo fish to investigate how aging affects several physiological traits and telomere length. They argue that these fish are excellent organisms for such a study because they are some of the longest-lived vertebrates (bigmouth buffalo fish can live for at least 112 years) and can be accurately aged by counting growth rings in hard internal structures known as otoliths or ‘earstones’.

Old but healthy

In fish ranging from 2 to 99 years old, the researchers measured stress response by checking the ratio of neutrophils to lymphocytes (NLR), which increases with stress. They also evaluated the immune system by measuring how effective extracted plasma was at killing bacteria, and, finally, they checked the length of telomeres. Each assay used samples from 80-100 fish from a variety of sites.

There was some variability between sites, which the researchers report pretty thoroughly in the paper, but the main takeaway is that none of the metrics declined significantly with age. Telomere length was steady, and older fish actually had an improved immune response and a lower NLR, meaning that they were less stressed. In other words, from a physiological perspective, older individuals of this extremely long-lived species are doing at least as well as younger ones and perhaps even better.

The researchers argue that this pattern fits well with the life history of the bigmouth buffalo. According to the ‘disposable soma’ theory, the evolution of aging is a balance in the trade-off between growth, self-maintenance, and reproduction. For many organisms, including humans, the potential benefits of being fertile late in life are offset by the likelihood that an individual will die before getting old and the fact that larger individuals – those who have grown more – aren’t more fecund. Bigmouth buffalo fish have no natural predators and become more fecund as they grown larger, shifting the balance of the equation. These differences in life history probably changed the selective pressures during their evolution, making it worthwhile to invest in self-maintenance even at a great age.

Although the pace of senescence varies considerably, the physiological systems that contribute to different patterns of senescence are not well understood, especially in long-lived vertebrates. Long-lived bony fish (i.e., Class Osteichthyes) are a particularly useful model for studies of senescence because they can readily be aged and exhibit some of the longest lifespans among vertebrates. In this study we examined the potential relationship between age and multiple physiological systems including: stress levels, immune function, and telomere length in individuals ranging in age from 2 to 99 years old in bigmouth buffalo (Ictiobus cyprinellus), the oldest known freshwater teleost fish. Contrary to expectation, we did not find any evidence for age-related declines in these physiological systems. Instead, older fish appeared to be less stressed and had greater immunity than younger fish, suggesting age-related improvements rather than declines in these systems. There was no significant effect of age on telomeres, but individuals that may be more stressed had shorter telomeres. Taken together, these findings suggest that bigmouth buffalo exhibit negligible senescence in multiple physiological systems despite living for nearly a century.

Conclusion

While the continued health of bigmouth buffalo well into old age is astounding, this isn’t a story about a set of biological traits or tricks that we can copy into humans to extend our lifespan. Rather, it’s a demonstration of the extreme variability that exists in senescence and the fact that age and senescence do not have to be linked. There are a handful of other vertebrates that show little senescence with age, but, in this case, there is no senescence and possibly even some improvement. Describing the pattern of senescence in extremely long-lived organisms is the first step towards understanding the mechanisms behind the variability of senescence, and manipulating those is the key to long life without old age, which is the ultimate goal of longevity research.

This is great news if you are a fish of course, but could humans do similar? We take a look at that possibility in our “Some Animals Don’t Age; We May do Likewise” article.

Literature

[1] Sauer, DJ, et al. No evidence of physiological declines with age in an extremely long‐lived fish. Scientific Reports (2021), doi: 10.1038/s41598-021-88626-5

Kizoo logo

Kizoo Technology Pledges €300 Million to Rejuvenation

It is always good to report on positive news for a change, and today is one of those happy occasions. Michael Greve, founder of Forever Healthy and Kizoo, has commited €300 million (just over $360 million at the time of writing) to support the development of rejuvenation biotechnology startups.

More support flowing in for technology to increase healthy longevity

There has been a steady increase in interest and funding for the field of rejuvenation biotechnology in the past few years. One of the key figures behind this is Michael Greve, the billionaire founder of Kizoo Technology Ventures and the non-profit Forever Healthy Foundation.

Michael Greve has become a tremendously positive force in the longevity movement, and his actions have funded a number of promising biotech companies focused on addressing the reasons we age.

He is also one of the driving forces behind the excellent Undoing Aging Conference held in Berlin. The Forever Healthy Foundation and SENS Research Foundation will be joining forces once again in May 2022 to host the premiere aging research conference in Europe, and we cannot wait to be there!

Funding the drive for increased healthy longevity

So far, Kizoo has funded grapeseed.bio, a life science accelerator program for startup companies targeting aging, Lysoclear, a company developing a novel molecular repair therapy to treat age-related macular degeneration (AMD) and restore lost vision, and Oisin Biotechnologies, a company developing a plasmid-based senescent and cancer cell destroying treatment.

The company is also funding ​AgeX Therapeutics, a biotech company developing tissue rejuvenation technology by targeting telomerase and tissue regeneration pathways, FoxBio, a company developing senescent cell-destroying therapies known as senolytics, and Elevian, which is developing therapeutics to stimulate regenerative capacity in our cells which is lost during aging. Kizoo is also supporting Turn Biotechnologies, which is developing therapies to reprogram aged cells back to being young cells using a technique known as partial cellular reprogramming. Partial cellular reprogramming has already been demonstrated to work in living animals, and now the race is on the translate that safely to humans.

Kizoo is also supporting LIfT Biosciences, which is aiming to create a cell therapy that can destroy all solid tumors regardless of strain or mutation; this company is using innately cancer-killing neutrophils to achieve what could potentially be a broad cancer therapeutic. In the cancer area with them is MAIA Biotechnology, which is focusing on creating cancer therapies that target novel pathways.

The SENS Research Foundation spinoff company Underdog Pharmaceuticals has also been supported by Kizoo. This company is targeting an oxidized form of cholesterol that accumulates inside macrophages, which eventually kills them and leads to the formation of plaques, the basis of heart disease. If successful, the harmful form of cholesterol could be removed from the macrophages, allowing them to return to healthy operation and ultimately keep our arteries healthy and free of plaques.

Recently, Kizoo funded the startup Revel Pharmaceuticals, a company based on a decade of research at Yale University seeking to break crosslinks in collagen fibers. Collagen provides our skin and tissues with structure, but as we age, it increasingly fuses with glucose to create stiff inflexible bonds known as crosslinks. These crosslinks cause our tissues to stiffen, including muscle, skin, and arteries, with disastrous health consequences, such as high blood pressure, lung damage, and skin wrinkles. Successfully breaking these crosslinks would remove that stiffening and restore tissue to healthy form and function.

Kizoo has also funded Cellvie, a company working on making mitochondrial transplantation a therapeutic reality. Mitochondria are the powerhouses of the cell, but as we age, they become increasingly dysfunctional and produce rising amounts of harmful free radicals, which can damage cells and mitochondria themselves. Cellvie plans to solve this problem by sending in fresh mitochondria to populate our cells and restore efficient energy production.

Last but not least, Elastrin is working on the issue of tissue and organ stiffening due to organ calcification thanks to support from Kizoo. This company is developing therapeutics that aim to restore calcified tissue and organs to a youthful, supple state again. Elastrin plans to target and restore degraded elastin by removing the harmful calcification that stiffens arteries.

As you can see, Kizoo has been instrumental in supporting the launch of a number of biotech companies targeting aging, and we are excited to see what else this injection of cash will bring.

The press release

Michael Greve, founder of the Forever Healthy Foundation and owner of Kizoo Technology Ventures, announced today that he will make available an additional €300 million to be invested in rejuvenation biotech.

The funds, to be deployed via Kizoo, will be used to create and support more startups in the rejuvenation space. They will also allow Kizoo to maintain a strong commitment to its key startups during follow-up rounds and to advance the therapies from clinical development to public availability.

With this €300 million commitment, Greve and Kizoo double down on their mission to accelerate the advent of rejuvenation biotechnology by doing lighthouse investments in entirely new, repair-based approaches that treat the root causes of aging and thus overcome age-related diseases. Through the creation of successful companies, they seek to inspire scientists, investors, and the general public by demonstrating that human rejuvenation is not science fiction anymore and that the resulting therapies are affordable and uncomplicated.

Technologies pioneered by Kizoo’s startups include removal of arterial plaque, decalcification of aged tissue, breaking of protein-glucose cross-links, and delivery of new mitochondria to aged cells – all aiming to prevent and repair common age-related conditions such as myocardial infarction, stroke, high blood pressure, tissue stiffening, skin aging, and loss of muscle function.

“I am really grateful that we can use the funds we have created with our highly successful technology ventures to contribute to the quest to get aging under full medical control and to make age-related diseases a thing of the past. For me, it is a worthy cause that is exciting in a technological, commercial, and above all, a humanitarian way” says Michael Greve.

Greve expects that the new funds, in combination with the strong, multi-round commitment of Kizoo to its key startups, should trigger co-investments of up to 3-4 times the initial amount, resulting in a significant acceleration of the development and public availability of the therapies.

For more information, please visit: forever-healthy.org

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.

Supplements

Developing a Science-based Personal Longevity Strategy

There is one common public reaction to my talks that bothers me quite a bit. I am worried that after each of my lectures, people will just start taking lots of supplements without regard for dosage or effectiveness, potentially hurting themselves in the process.

This is because one of the most common reactions to me mentioning any currently available interventions is to search for each and every component and order them all right away. Whatever I say about safety and the need to test before people make any changes in their lifestyles seems ineffective.

So, I want to talk about this problem.

Do you know exactly what science is and why we use science rather than faith, fantasy, intuition, or chance to create every physical thing we have?

Science is a set of procedures used for knowledge gathering, accumulation, classification, assessment, and application that makes it possible to get reproducible (read – controllable) results. The scientific method allows us to build houses that don’t collapse, make planes that can fly, produce edible food, and create medicines that can cure diseases.

Once you step away from that and ignore the scientific method, your results become uncontrollable, which is what happens when you run to the store to buy longevity supplements without any preliminary homework.

The need to self-experiment carefully

Yes, most of the advanced life extensionists began from this point, myself included, blindly taking a handful of supplements without checking up on their effects. However, this stage should be as short as possible for two reasons.

SupplementsThe first reason is that geroprotectors are having more and more effects. Some of them are drugs with systemic effects on the body – and adverse effects, too.

Think of a car driven by a blind driver. If the maximum speed is low, the potential harm is relatively low as well. The driver might get a couple of scratches and bruises, that is all. However, as the speed increases, the possibility of being seriously harmed by the collision increases as well. I don’t know anyone who would dare to get a ride from a blind driver at, say, 60 mph.

Yet, when you intend to take a huge list of longevity pills and therapies without any sort of analysis or control, this is exactly what you are doing.

SupplementsThe second reason is that everyone is different. What works for another person with another genetic portrait may not work well for you. You might not need it at all (for instance, my lipid profile is so damn perfect that it does not make sense to intervene in it with statins and diet), or you may need the opposite of what you are planning to do (for example, if your level of vitamin D is too high already, you’ll have to suppress it rather than taking vitamin D as a supplement).

However, you will never know which interventions are appropriate for you if you don’t get tested to learn your starting points.

This call would be incomplete without some sort of advice. What would I suggest for beginners?

Genetic testing

Learn all you can about your genome, including weaknesses, strong points, potential drug sensitivities and health risks, as this will inform your lifestyle much better than common sense.

Study your biomarkers of aging

Have your blood tested in detail before you self-prescribe any treatments, as this will help reveal where to focus your attention. I am really happy to have the Open Longevity project here in Moscow; this organization collected a list of the most useful biomarkers, and people can get tested two or three times per year to see the way they age. Check its presentation for the recommended list of biomarkers.

Talk to a professional about your results

Doctors know more than you about the human body. They can see what you can’t see, they can warn you about biometric deviations that represent serious problems, and they can calm you down about other perceived issues that are only the short-term consequences of what you were doing yesterday. In my case, high levels of inflammatory signals were provoked by going to a swimming pool the day before. I was worried by the numbers until I was told that next time I should do my test three or four days after the last episode of intensive physical activity.

Introduce new supplements one at a time

I know that you will be taking supplements without medical supervision. I know that for a fact. I can’t talk you out of it because there are not enough doctors who are able to make this journey to longevity with you. I beg you, please, think about introducing one new supplement into your regimen every two weeks instead of taking a handful at once. That way, you will know how this particular compound affected you and what changes it made in how you feel. Similarly, whenever you begin taking something, take a low dose for the first few days. Why? This is easy: individual intolerance is a possibility. You can accidentally find out that you are intolerant to a specific compound. If the dose is small, it will be enough to find out about the intolerance but not enough to severely harm yourself.

Make your longevity checkups regular

Save some money to do it at least twice per year. This way, you will know what is happening, you can track the changes, and you can check if the strategy you chose is still good and make sure that you did not overdo it. Like in the example with vitamin D, by trying to remove the deficiency, you can get an excess, which is as harmful as a deficiency. Make sure that you have found a healthy medium.

Accumulate the information, and make it visual

Collect the results of your tests, build graphics based on them, see what is changing, and become aware of why. This feedback loop will motivate you to support lifestyle improvements or to be less fanatical about what you are doing if you are doing too much.

Conclusion

This is about all I have to say. I know that this does not sound easy nor very comfortable. However, this is a way to reduce risks and get more health benefits from your life extension activities. Caution, patience, and self-discipline should be the main pillars of your strategy.

There is one more thing. Try not to discredit our movement. Remember that if you accidentally hurt yourself, or if you cannot prove that you achieved results, this alone makes it hard for us as a community to persuade others that we are doing something useful. It is much easier to promote rejuvenation research if you can prove that your evidence-based longevity strategy has caused your body to age more slowly and given you better than average health for your age. Trust in science, and hopefully, in 30 years, you will be younger than you are now.

Young rat

Vibration Reduces Cellular Senescence in the Bones of Rats

A new study published in the journal Aging has examined the effects of vibration on cellular senescence and osteoporosis.

Superior treatments are needed for osteoporosis

Typically, bone density peaks for individuals around age 30 and then declines with age. While osteoporosis is rarely a direct cause of death, it is a major cause of disability. It can also indirectly cause death, as a rapid decline in health after a bone fracture is common in older individuals. However, as is the case with most age-related diseases, the current treatments and preventative strategies for osteoporosis are inadequate.

Low-magnitude vibration has been shown to be beneficial for bone growth in a variety of contexts. As a treatment, it is appealing due to its low cost, low side effect profile, and its ability to be utilized even in patients who cannot participate in load-bearing exercises.

Longevity researchers have also investigated whether senotherapeutics may help alleviate osteoporosis. In mice, cellular senescence has been shown to play a causal role in osteoporosis. Clearance of these senescent cells has also been shown to increase the bone density of osteoporotic mice.

Good vibrations

The Liang Li lab at Sichuan University recently took these two lines of research a step further, investigating the interplay between osteoporosis, cellular senescence, and low-magnitude vibration in rats [1]. Young (3-month-old) and old (22-month-old) rats were used in the study. Bone marrow mesenchymal stem cells, osteoblasts, and osteocytes were isolated from the rats and used for in vitro experiments. All three cell types showed greater degrees of senescence when taken from the older cohort, with more DNA damage, lower proliferation rates, and an increase in the senescence markers p21, p16, and SA β-gal.

Applying a vibration of 0.3 g (30% that of gravity) at a frequency of 90 Hz (similar to that of a cat’s purr) to these cells reduced their senescent phenotypes. Osteoblasts benefited from the vibration treatment in particular, showing similar DNA damage, SA β-gal activity, and p21 expression to cells isolated from young rats. The same vibration applied to aged rats also proved to be beneficial. Aged rats showed greater bone density as measured by both CT scanning and postmortem histology, although senescence markers were not examined.

With aging, the osteogenic cells in the bone microenvironment exhibit aging changes and the decline in proliferation and functional activities. The osteocytes have the most obvious aging changes. However, the LMV can inhibit the senescence of osteogenic cells partly through the Sirt1/p53/p21 axis, thus promoting bone formation of aged rats. Therefore, the inhibition of osteogenic cell senescence by LMV, is a valuable treatment to prevent or delay osteoporosis.

Conclusion

Our bones respond considerably to repeated impact. It is well studied that astronauts lose bone mass while in space and that running and walking can help stave off osteoporosis. Similarly, vibration-induced bone growth is a well-known phenomenon. However, this study is the first to show that the link between low-magnitude vibrations and bone formation extends to cellular senescence. It is unclear from this research what mechanisms are at play to create the link between the two, but this should provide an interesting line of future research.

In humans, the effectiveness of whole-body vibration is also not clear. It has improved bone density in some, but not all, clinical trials, suggesting that it only has a mild to moderate impact. Further, while maintaining bone density is crucial to extending healthspan, vibration does not seem to be a great candidate as an anti-aging therapy. One of the greatest advantages of a longevity-based approach is its application to all the tissues in the body, and while the authors of this study did not investigate the effect of vibration on other organs, it seems logical that these effects would apply only to bone tissue. However, it would be an extremely valuable development if vibration were to be discovered to impact cellular senescence in other tissues 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.

Literature

[1] Wen, J., Bao, M., Tang, M., He, X., Yao, X., & Li, L. (2021). Low magnitude vibration alleviates age-related bone loss by inhibiting cell senescence of osteogenic cells in naturally senescent rats. Aging (Albany), 13(8), 12031-12045. https://doi.org/10.18632/aging.202907

A long-eared, long-tailed mouse

Rapamycin Reduces Age-Related Hearing Loss in Mice

Researchers have found that rapamycin supplementation attenuates but not reverses age-related hearing loss in mice, even if the treatment starts later in life [1].

Hear ye, aging is coming

Gradual hearing loss might not be as physically harmful as cancer, Alzheimer’s or many other age-related pathologies, but even with the newest hearing aid technology, it can be detrimental to our emotional health and to the quality of our contacts with the outside world. In multiple studies, age-related hearing loss has been linked to depression [2] and dementia [3]. It is also one of the most widespread age-related pathologies: approximately one in three people between the ages of 65 and 74 has hearing loss, and nearly half of people older than 75 have difficulty hearing.

Age-related hearing loss has been associated with the decline in the number of healthy hair cells. Despite their name, these have nothing to do with human hair; instead, hair cells reside in our cochlear and transform the vibration of the cochlear-filling liquid into electrical impulses using bunches of hair-like filaments. The impulses then enter the nervous system to be registered as sound. Unlike birds and fish, humans and other mammals are generally incapable of regrowing hair cells.

Rapamycin: a not-so-new hope

Rapamycin is probably the most promising compound currently studied by longevity researchers. Discovered decades ago, rapamycin has repeatedly demonstrated its ability to drastically prolong life in various model organisms and to attenuate many age-related pathologies. Rapamycin targets mTOR (mechanistical target of rapamycin), a protein that plays an important role in nutrient sensing. The dysregulation of nutrient sensing pathways – that is, the growing inability of a cell to correctly detect the amount of nutrients available and to adjust its activity accordingly – is a hallmark of aging. Rapamycin is also one of the few potential age-reversing agents currently in human trials.

Rapamycin has been shown to have a major effect on the prevalence of cancer, cardiac diseases, cognitive decline, macular degeneration, and other age-related conditions. So, it was only a matter of time before age-related hearing loss gets caught in researchers’ crosshairs.

Effective even later in life

In their previous research, the same researchers found that age-related hearing loss was alleviated in mice who had been receiving rapamycin since they were young. In this new study, the scientists wanted to see whether these results could be replicated in mice that only began to receive rapamycin-laced food later in life. It is worth noting that one of the most hope-inspiring aspects of rapamycin is its ability to offset aging in model organisms even when the treatment starts relatively late.

Hearing loss is measured by the so-called TS (threshold shift). It gauges how much air pressure at a certain frequency is enough for the animal to hear the sound, relative to a baseline, which, in this study, was measured at the age of 5 months. As mice age, they need sound to be louder (more air pressure) for their brains to register it.

In this study, healthy mice were divided into a study group and a control group at the age of 14 months, which roughly corresponds to 50 human years. The study group then began receiving food enriched with rapamycin.

The researchers found that rapamycin significantly rescues hearing over the remaining lifespan of the mice. Interestingly, this effect seemed to wane for the lowest measured frequency (4Hz) in the oldest mice. The reason is probably that hair cells at the top part of the cochlear, where low frequency sounds are registered, are known to begin to atrophy earlier. This led the researchers to conclude that rapamycin does not reverse but rather attenuates age-related hearing loss.

Generally, research shows that rapamycin has a slightly stronger life-prolonging effect on female mice compared to males. In this particular study, though, the researchers did not detect any sex-related differences in its effects.

Quantity or quality?

In a seeming paradox, the researchers also did not detect less hair cell loss in the rapamycin-fed animals. In the absence of an obvious reason for that, the authors hypothesize that, rather than promoting the survivability of hair cells, rapamycin helps to maintain the function of the cells that remain.

The researchers did not analyze the molecular underpinnings of the rapamycin-induced hearing loss attenuation, though they suggest several possible pathways. One of them is based on rapamycin’s ability to positively affect the endoplasmic reticulum (ER) [4], the ribosome-hosting organelle in charge of protein production. ER stress has been linked to age-related hearing loss [5].

Conclusion

The ability of rapamycin to attenuate age-related hearing loss reinforces the emerging understanding that rapamycin works on a fundamental level, affecting common cellular pathways that induce various aging-related pathologies across an organism. On the other hand, the failure to reverse hearing loss tells us that rapamycin is far from being the miracle cure that we need to defeat aging. To do this, science will probably need to develop a much more complex and integrated approach.

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.

Literature

[1] Altschuler, R. A., Kabara, L., Martin, C., Kanicki, A., Stewart, C. E., Kohrman, D. C., & Dolan, D. F. (2021). Rapamycin Added to Diet in Late Mid-Life Delays Age-Related Hearing Loss in UMHET4 Mice. Frontiers in Cellular Neuroscience, 15, 100.

[2] Brewster, K. K., Ciarleglio, A., Brown, P. J., Chen, C., Kim, H. O., Roose, S. P., … & Rutherford, B. R. (2018). Age-related hearing loss and its association with depression in later life. The American Journal of Geriatric Psychiatry, 26(7), 788-796.

[3] Liu, C. M., & Lee, C. T. C. (2019). Association of hearing loss with dementia. JAMA network open, 2(7), e198112-e198112.

[4] Cho, B. J., Hwang, J. S., Shin, Y. J., Kim, J. W., Chung, T. Y., & Hyon, J. Y. (2019). Rapamycin rescues endoplasmic reticulum stress–induced dry eye syndrome in mice. Investigative ophthalmology & visual science, 60(4), 1254-1264.

[5] Hu, J., Li, B., Apisa, L., Yu, H., Entenman, S., Xu, M., … & Zheng, Q. Y. (2016). ER stress inhibitor attenuates hearing loss and hair cell death in Cdh23 erl/erl mutant mice. Cell death & disease, 7(11), e2485-e2485.

Eye

Phase 2 Trial Of Gene Therapy For Diabetic Macular Edema

Following a significant adverse event in which a patient lost vision in an eye treated with ADVM-022, Adverum Biotechnologies has unveiled the details of its Phase 2 trial of this gene therapy for diabetic macular edema.

An overgrowth of blood vessels

Wet age-related macular degeneration (AMD) is caused when blood vessels from underneath the retina begin to grow into it. When these vessels leak fluid into the retina, it results in macular edema. This problem is also frequently associated with diabetes, as it causes damage to the small blood vessels within the retina; this problem is known as diabetic macular edema (DME).

The immediate cause of wet AMD is vascular endothelial growth factor (VEGF), which encourages the development of abnormal blood vessels within the retina. Therefore, it is no surprise that the current standard of care for wet AMD is a regular injection of anti-VEGF drugs, such as afilbercept, which binds to VEGF more tightly than natural receptors [1].

A gene therapy to replace regular injections

The purpose of ADVM-022 is to cause cells in the eye to express afilbercept themselves, obviating the need for injections of anti-VEGF drugs directly into the eyeball every four to twelve weeks. Ideally, this would solve problems with patient compliance and regular administration of expensive drugs, and it would require considerably fewer visits to the doctor’s office.

In a previous Phase 1 trial, ADVM-022 caused only mild and moderate side effects at both low and high doses. At the lower dose, inflammation was mild and responded well to steroid eyedrops.

This new Phase 2 trial has enrolled 36 patients, comparing low-dose and high-dose ADVM-022 against direct injections of afilbercept. In this study, an unexpected adverse event occurred; one patient lost fluid and vision in the treated eye while experiencing extreme inflammation. It is not yet known what role ADVM-022 played in this event.

Conclusion

Wet AMD is a serious, progressive age-related disease that afflicts millions of people, and while forcing the expression of a specific protein to stop blood vessel growth is a less-than-ideal solution for people who wish to see its root causes dealt with, the idea that we can use gene therapies to cure age-related diseases is certainly appealing. We hope that the adverse event reported in the Phase 2 trial was very rare or unrelated and that such a gene therapy is suitable for replacing simple afilbercept, or other anti-VEGF, injections as the standard of care.

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.

Literature

[1] Browning, D. J., Kaiser, P. K., Rosenfeld, P. J., & Stewart, M. W. (2012). Aflibercept for age-related macular degeneration: a game-changer or quiet addition?. American journal of ophthalmology, 154(2), 222-226.

Rejuvenation Roundup April

Rejuvenation Roundup April 2021

We’ve all aged another month, but we’re another month closer to discovering how to reverse it. Here’s what we’ve learned about aging in the month of April.

LEAF News

Promising to connect biotech innovators and investors, researchers and policymakers, the Longevity Leaders World Congress will start tomorrow and continue through Friday. It will focus on aging science, aging well, and financing of longevity. Content access will be free; 1:1 partnering will be available for different levels of paid registration.

Political Outreach

Elderly people road signThe All-Party Parliamentary Group on UK Healthcare Equality: The APPG’s new initiative aims to close the life expectancy gap, address health inequality in the UK, and foster a preventative approach to healthcare to support healthy longevity.

The Senate Special Committee on Aging Needs Better Focus: In this op-ed, Breanna Deutsch informs us that the United States Senate has a Special Committee on Aging but that it has little to do with the actual processes of aging.

Elderly crowdEU Green Paper on Aging Falls Short of the Mark: Steve Hill explains that, similar to the situation in the United States, this green paper makes no mention of the potential of therapies that seek to target the aging processes directly.

Lifespan News

AI for Longevity Drugs: A new company using AI and deep learning for longevity drug development, the regrowth of missing teeth in mice, and to grow human muscle tissue in pig embryos. We also discussed a new means of stopping colorectal cancer from proliferating.

Depression and Aging: The GrimAge clock showing that major depression accelerates aging, the NIH’s project to study senescent cells, research on the pace of aging, brain cells and DNA repair, and selenium supplementation’s effects on obesity in mice.

CRISPR Epigenetic Breakthrough: A new CRISPR breakthrough, the creation of new neurons from astrocytes in vivo, the Dog Aging Project on Science to Save the World, serum albumin increasing lifespan in a mouse study, and the effects of hypoxia on the SASP.

European Longevity Initiative: The European Longevity Initiative, the effects of spermidine on cognitive function, diet and exercise to reduce epigenetic age, B-cell depletion for ameliorating Alzheimer’s, and RNA deep sequencing that monitors the progression of Parkinson’s disease.

Science to Save the World

Rejuvenation Roundup Podcast

Ryan O’Shea of Future Grind hosts this month’s podcast, showcasing the events and research discussed here.

Advocacy

Some Animals Don’t Age; We May Do Likewise: Some marine species are negligibly senescent: they do not noticeably deteriorate over time.

The “Not in my Lifetime” Argument: It used to be completely impossible, but rejuvenation biotechnology has grown from a fictional dream into a quickly growing field

Some people think longer lives would cause loss of motivationIncreased Longevity and Lost Motivation: The idea that healthy longevity would deprive us of motivation in life is incredibly bizarre.

Increased Longevity and Cultural Stagnation: Try explaining to your grandfather that he has to put up with heart disease because we’re afraid that people his age may all become troublemakers if allowed access to life-extending technologies.

Rejuvenation is Not Immortality: The most intuitive, commonly accepted meaning of “immortality” is that it describes someone who cannot die at all.

Increased Longevity and Overpopulation: Since the 1960s, both birth rate and population growth have been gradually falling.

Are There More Urgent Issues Than Aging?: 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.

Some People Worry that Longer Lives Mean Longer Decrepitude: This concern is based on the ancient Greek myth of Tithonus, which might be thought of as a cautionary tale of the alleged inherent dangers of indefinite longevity.

Summaries

Chamomile is a great source of Apigenin.A Summary of Apigenin: Found in chamomile, this flavonoid has traditional uses that can be biochemically explained.

A Summary of Niacin (Nicotinic acid): Recent human trials have shed new light on its possible role of niacin in addressing mitochondrial dysfunction and aging.

Blood-brain barrierThe Blood-Brain Barrier’s Role in Brain Aging: As Nina Khera explains, research suggests that the degradation of the blood-brain barrier over time is a factor in the development of brain diseases.

Research Roundup

New CRISPR Technology Allows Turning Genes Off and On Again: Directly affecting methylation sites across the genome allows for precise targeting of epigenetic changes.

Many foods contain selenium such as nuts, eggs, mushrooms, and some meats.Selenium Supplements Protect Against Obesity in Mice: A recent study has shown that mice given selenium supplements were protected against the effects of a high-fat diet, similar to mice with a restricted methonine intake.

A Non-Invasive Biomarker to Track Cellular Senescence: A lipid metabolite could serve as a novel biomarker to test the performance of senolytics, according to a new study. Such a biomarker can be detected from blood or urine.

AlbuminResearchers Claim Serum Albumin Increases Mouse Lifespan: Researchers behind a new manuscript claim that the lifespans of middle-aged mice can be increased up to 20% with a treatment of recombinant serum albumin every 3 weeks.

Researchers Convert Astrocytes to Neurons in Vivo: This technique paves the way for possible future brain regeneration therapies.

Hypoxia Reduces SASP Without Reducing Senescent Cell Burden: A new study in Molecular Cell has shown that the benefits of hypoxia may be derived from a suppression of the inflammatory SASP.

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.

Vegetables contain many important nutrients that support longevity.Diet, Exercise Reduce Epigenetic Age in 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.

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-ß removal.

Spermidine supplement may slow down aging.Spermidine for Cognitive Function in Flies, Mice, and Humans: Recently published research in Cell Reports provides a detailed account of dietary spermidine improving cognition and mitochondrial function in flies and mice

GrimAge Links Aging and Major Depression: People with major depressive disorder may have biological ages that are two years over their chronological ages.

Muscle fibersNMN Human Trial Suggests Improved Muscle Glucose Metabolism: Administration of NMN appeared to improve the ability of insulin to increase glucose uptake in skeletal muscle.

Qigong Attenuates Age-Related Cognitive Decline in Trial: This traditional practice was found to have substantial physical benefits for the brain.

Smell of FoodSmelling 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.

Drug Allows Healing Without Scars in Mice: 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.

17-a-estradiol late in life extends lifespan in aging UM-HET3 male mice: In genetically heterogeneous mice, the “non-feminizing” estrogen 17-a-estradiol extended median male lifespan by 19% in this study.

Effect of long-term treatment with C60 fullerenes on the lifespan and health status of CBA/Ca mice: The researchers suggest that the protective effect of fullerenes is in opposition to the negative effect of olive oil in CBA/Ca mice.

Nicotinamide mononucleotide and melatonin counteract myocardial ischemia-reperfusion injury: This combination was shown to activate SIRT3/FOXO1 and reduce apoptosis in aged male rats.

Rapamycin Added to Diet in Late Mid-Life Delays Age-Related Hearing Loss in UMHET4 Mice: The results show that a later life addition of rapamycin can decrease age-related hearing loss in the mouse model, however, it also suggests that this decrease is a delay/deceleration rather than a complete prevention.

Rapamycin restores brain vasculature, metabolism, and blood-brain barrier in an inflammaging model: These results indicate that rapamycin may play an important therapeutic role in inhibiting neuroinflammation by normalizing brain vascularity, BBB, and some brain metabolites, and it has a high translational capability.

No evidence of physiological declines with age in an extremely long-lived fish: Bigmouth buffalo may be negligibly senescent.

The COVID-19 Pandemic Appears to Have Increased Longevity in Japanese Centenarians: The protective measures put in place also protected these elderly people against other viruses.

50 years of the “war on cancer”: lessons for public health and geroscience: The year 2021 marks the 50th anniversary of the National Cancer Act of 1971 and President Richard Nixon’s declaration of a “war on cancer”.

Hyperbaric oxygen therapy effectively alleviates D-galactose-induced age-related cardiac dysfunction in pre-diabetic rats: This study shows that this therapy reduced metabolic impairments and mitochondrial dysfunction while increasing autophagy, resulting in an improvement of cardiac function in aged pre-diabetic rats.

Low-magnitude vibration alleviates age-related bone loss by inhibiting cell senescence of osteogenic cells in naturally senescent rats: After this treatment, the number of osteogenic cells staining positively for senescence-associated ß-galactosidase (SA-ß-Gal) decreased significantly.

News Nuggets

VitaDAOVitaDAO to Launch Longevity Biotech by Democracy: VitaDAO will aim to fund longevity research, give its members ownership of the resulting IP, and allow members to vote on the direction of the organization.

SenNet: The NIH Large-Scale Cellular Senescence Initiative: The National Institute of Health is going all-in on cellular senescence with its recently announced SenNet program. We asked two of the leading experts in aging research to weigh in on this initiative.

Biotech investmentJim Mellon’s Funding of Longevity Projects: How does an idea that is too unconventional for mainstream channels get funded? Often, even venture capitalist firms are too risk-averse, and government funding agencies are too entrenched in the status quo.

FDA-Approved Drug Is a Candidate for Dry AMD Treatment: Researchers have determined that directly improving autophagy through flubendazole is potentially useful in treating dry age-related macular degeneration, a disease that causes vision loss.

BioAge logoBioAge Off to a Rapid Start in 2021: 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.

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Some people think life extension would lead to resource shortages.

Some Argue that Increased Longevity Would Cause Scarcity

The discussion of increased lifespans through medical and technological methods of addressing the various processes of aging raises the concern that this could lead to a lack of resources and result in conflict and suffering.

The argument suggests that we will run out of resources if we develop the technology to treat age-related diseases. Proponents of this line of thinking believe that food, water, energy and other resources will dwindle in such a world and that it would lead to global conflict.

However, such arguments often do not take into account progress in food production, water filtration, renewable energy and other technological advances that could potentially offset these problems.

Let us look closely at the data and see if these concerns are warranted.

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

  image29  

Fig 1.  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. But 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 [1], but once again, no famine caused by the deficiency of global food production followed [2]. 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 rapidly. 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 2017 Hunger Map by the World Food Program, illustrating the progress.

World hunger map 2020

Fig 2. World Hunger map 2020 by the WFP

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.

years

Fig 3.  Food supply 1965 vs 2007 Source: Gapminder statistics (www.gapminder.org/)

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).

New Technologies for increased food production
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 isfarm-1554327_1280sues.

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 [3].

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 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 [4]. 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 [5].

Meat without cattle farming

As animal farming represents the major source of land degradation, water expenditures, and pollution, global society is determined to find a solution. This intention is strongly supported by the movement to reduce animal suffering. Today, there are many companies engaged in the creation of lab-grown meat, animal-free dairy products and hen-free eggs. Let’s see what happens in the lab-grown meat production field.

The first burger with lab-grown meat was created back in 2012 and has cost about $330,000, which was used to carry on the corresponding studies and to produce enough meat so that it could be cooked and tasted. The chief scientist behind the first cultured hamburger, Professor Mark Post of Maastricht University, is dedicated to find a way to reduce the costs of production in order to make the meat affordable to everyone. It is expected to enter the market in the next few years at a price of $80 per kilogram.

image38The team behind the project believes that cultivated meat could be a viable solution for the food crisis and could satisfy the world’s growing demand for meat without animal suffering and harm to the environment. This is only one example.

Startups like Super Meat and Memphis Meats are working on the same problem. Making a laboratory into a farm is beneficial in many ways, including 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 such as adding 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 use of preservatives. The same system can be used to grow fish, shrimp, and frog meat as well, thus reducing the impact of fishing and fish-farming on the environment.

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. The main trade-off for implementing this new technology is the same as with hydroponics: more energy usage [6].

GMO Crops

Another solution to global demand and a path to a “second Green Revolution” is the use of genetically engineered (known as GE or GMO) crops designed to produce greater yields, resist diseases and grow in conditions not favorable to organic crops.

There is currently a lot of debate about the use of GMO crops to improve yields and keep pace with food demands globally, and some argue that organic crops are superior environmentally and are better nutritionally. However, if we examine the data, we will see that this is far from the case and that this is perpetuating agricultural myths [7].

genebank4_4331057760GMO critics often claim that organic farming practices use less synthetic pesticides that have been found to be ecologically damaging [8]. However, factory organic farms also use their own range of natural pesticides, that are still damaging [9].

To add to the problem, they refuse to endorse technologies that might reduce or eliminate the use of these altogether, such as genetic modification to make them resistant to insects and other pests. In comparison, GMOs have the potential to boost crop yields, increase nutritional value, and generally improve farming practices while reducing synthetic chemical use.

For example, there are sweet potatoes being engineered to be resistant to a virus that currently decimates the African harvest every year; this could feed millions in some of the poorest nations in the world if their crops did not suffer from this blight [10].

Science has created carrots high in calcium to fight osteoporosis and tomatoes high in antioxidants. In fact, it is as important what we put into a crop as what we take out.

Potatoes can be modified so that they do not produce high concentrations of toxic glycoalkaloids, and nuts can be modified to lack the proteins which cause allergic reactions. Despite this, organic proponents refuse to even give GMOs a fair chance, to the point of hypocrisy.

For example, organic farmers apply Bacillus thuringiensis (Bt) toxin (a small insecticidal protein from soil bacteria) on their crops every year, and they have for decades. It’s one of the most commonly used organic pesticides by organic farmers and is not harmful to mammals. Yet, when genetic engineering is used to place the gene encoding the Bt toxin into a plant’s genome, the resulting GMO plants are then vilified by the same people willing to spray the exact same toxin that the gene encodes for over the exact same species of crop!

Nutritionally, the FDA has concluded there is no significant difference in nutrition between organic and GMO produce and considers GMO foods safe for human consumption despite the pressure from certain groups suggesting that they are not. The FDA concludes, “Credible evidence has demonstrated that foods from the GE plant varieties marketed to date are as safe as comparable, non-GE foods.” Additional studies also confirm this [11].

The World Health Organization also concludes that GM foods, “currently available on the international market have passed safety assessments and are not likely to present risks for human health. In addition, no effects on human health have been shown as a result of the consumption of such foods by the general population in the countries where they have been approved”.

Ecologically, GMO is a better solution, as it reduces the amount of toxin being used and thus leaching into the surrounding environment and waterways. Other GMOs have similar goals, like making crops tolerant to occasional flooding, which can replace herbicide use as a means of killing weeds. If the goal is to protect the environment, then why not incorporate the new technologies that help us do that?

But the real reason organic farming isn’t more green than conventional is that, while it may be better for local environments on a small scale, organic farms produce much less food per per mile than conventional ones. Organic farms produce around 80% of the products of a conventional farm [12], with some studies showing yields as low as 50% less!

Right now, there are millions of people suffering from hunger and malnutrition, and many of those will die from it [13]. If we were to switch to entirely organic farming, the number of people suffering would increase by 1.3 billion, assuming we use the same inefficient amount of land we use now for organic farming.

barley-872000_1920So, if we switched to all organic farming, further ecological damage would likely be caused by the creation of new farms and additional space for organic crops. This would cause the destruction of currently untouched habitats by ploughing over the wild habitats we have left, which would threaten wildlife. This is all due to the poor space/efficiency ratio of organic farming.

So far, we have already cleared more than 35% of the Earth’s ice-free land surface for agriculture, an area 60 times larger than the combined area of all the world’s cities and suburbs. Barring the last ice age, nothing has been more disruptive to the planet’s ecosystem and its inhabitants than agriculture.

What would happen to what’s left of our planet’s wildlife habitats if we needed to remove another 20% or more of the world’s fertile land to accommodate for organic farming? Unfortunately, until organic farming can rival the production output of conventional farming and GMO crops, its ecological cost due to the need for space will be devastating.

As bad as the pesticides and fertilizers polluting the world’s waterways from conventional agriculture are, it’s better, ecologically speaking, than destroying those key habitats altogether.

This is not to say that there’s no hope for organic farming; better technology could help to overcome the production gap, allowing organic methods to produce on par with conventional agriculture. If that did occur, then organic agriculture would become a lot more ecologically sustainable.

However, to present organic farming as the be-all and end-all of agriculture is a huge misconception and perpetuates the agricultural myths that lead to hatred of GMOs without sufficient understanding of the scientific and ecological reasons for using them.

Yes, but what about water?

While our world is often called the blue planet because most of its surface is covered with water, freshwater is only about 3% of this amount. Up to 90% of the Earth’s fresh water is represented by polar ice caps. The main sources of fresh water available to use are groundwater (springs, boreholes) and surface water (rivers, lakes), while atmospheric water is much harder to use.

It is important to note that there has been 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 percent to 91 percent. 2.6 billion people have gained access to an improved drinking water source since 1990.

Improved drinking source means a source of water protected from external pollution causes, such as animals and bird droppings. Improved drinking sources, such as piped water, tubewells and boreholes, provide water that is safe to drink, while unimproved sources, such as rivers, lakes, and other sources open to external pollution, can be a threat to people’s health.

The MDG target of 88 percent 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 percent coverage, compared with 23 in 1990 [14].

However, the global population keeps growing, the need for food is increasing, and the current agricultural methods lead to a corresponding increase of water expenditures. Another challenge is climate change: as temperatures rise, many regions are facing unusual weather phenomena or are suffering from the aggravation of existing weather, such as floods and droughts – especially the latter.

There are two main ways to ensure water resources for the growing population:

  • To save as much water as possible (by using hydroponics and other techniques that reduce evaporation instead of traditional farming; by using lab-grown meat instead of animal farming; by collecting and effectively cleaning sewage; by reducing water losses due to damaged pipelines or irrational water usage)
  • To develop and implement new ways of fresh water production (desalination plants, water collection from the air and others).

A project in Israel is an example of how human creativity can solve the problem of water scarcity in a given country in just 10-20 years. Israel is located in a region with a subtropical mediterranean climate, with long, droughty summers and relatively low precipitation during the winter. There are only few natural water sources (lakes and rivers), which Israel shares with its neighbors, but their capacities are used almost completely, which is leading to their exhaustion and the Dead Sea levels lowering by one meter every year.

waterplan-2

In order to ensure effective agriculture, the country needs to use a significant amount of fresh water for irrigation. Despite the usage of advanced technologies (drop irrigation, water-retaining grounds), in 2004-2008, Israel was faced with drought, and it became clear that the natural water resources could not ensure stability anymore.

As a result, the government decided to invest in a desalination plant’s construction, and currently about 50% of Israel’s overall needs for fresh water are provided by 5 desalination plants located on the Mediterranean coast and providing enough fresh water for more than 4 million people.

Fresh water produced in Israel by desalination is also cheap (around $30 per household a month, similar to most US households). The technology has proven to be so efficient that the Israeli desalination company is now building several new plants in other countries to help them solve the water scarcity problem.

In California, a new desalination plant is going to provide about 7 percent of the drinking water needs for the San Diego region. If we built several thousand desalination plants of this capacity, it could fulfill the unmet fresh water needs of the global population completely.

It is planned to build more desalination plants in Israel, and some of them are going to deliver the byproduct of desalination – salt water – to the Dead Sea, to compensate the exhaustion of the rivers feeding it. This ambitious project includes the construction of a water-power plant, powered by a waterfall, to the Dead Sea. Furthermore, the technologies Israel is using to clean the sewage are so powerful that up to 86% of the water is recycled and brought back to be used for irrigation and other needs. The next leader in sewage recycling is Spain – with only 19% of sewage water recycled.

Israel is not the only country with a positive experience of desalination. From 2006 to 2012, after a period of consequent droughts, Australia brought six desalination plants online, investing more than $10 billion. There are plants in Bahrain, Japan, Saudi Arabia, China and many other countries.

This example is meant to show that there already is a number of technical solutions to the water problem. The question is whether there will be enough social support and political will to massively implement them and establish more rational and environment-friendly processes of fresh water production, consumption, and recycling.

Conclusion

Given the march of technology and that we are already well ahead of demand, it is highly unlikely that we will be running out of resources in the near future.

Literature

[1] United Nations, Department of Economic and Social Affairs, Population Division (1999). The World At Six Billion. ESA/P/WP.154. [2] Gráda, C. Ó. (2007). Making famine history. Journal of Economic Literature, 45(1), 5-38. [3] FAO, U., & Steinfeld, H. (2006). Livestock’s long shadow: Environmental issues and options. Rome:[sn]. [4] 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. [5] REN21. 2016. Renewables 2016 Global Status Report (Paris: REN21 Secretariat). [6] Mattick, C. S., Landis, A. E., Allenby, B. R., & Genovese, N. J. (2015). Anticipatory Life Cycle Analysis of In Vitro Biomass Cultivation for Cultured Meat Production in the United States. Environmental science & technology, 49(19), 11941-11949. [7] Hielscher, S., Pies, I., Valentinov, V., & Chatalova, L. (2016). Rationalizing the GMO Debate: The Ordonomic Approach to Addressing Agricultural Myths. International journal of environmental research and public health, 13(5), 476. [8] Aktar, W., Sengupta, D., & Chowdhury, A. (2009). Impact of pesticides use in agriculture: their benefits and hazards. Interdisciplinary toxicology, 2(1), 1-12. [9] Bahlai, C. A., Xue, Y., McCreary, C. M., Schaafsma, A. W., & Hallett, R. H. (2010). Choosing organic pesticides over synthetic pesticides may not effectively mitigate environmental risk in soybeans. PLoS One, 5(6), e11250. [10] Qaim, M. (1999). The economic effects of genetically modified orphan commodities: projections for sweetpotato in Kenya. ISAAA. [11] Dangour, A. D., Lock, K., Hayter, A., Aikenhead, A., Allen, E., & Uauy, R. (2010). Nutrition-related health effects of organic foods: a systematic review. The American journal of clinical nutrition, 92(1), 203-210. [12] Mäder, P., Fliessbach, A., Dubois, D., Gunst, L., Fried, P., & Niggli, U. (2002). Soil fertility and biodiversity in organic farming. Science, 296(5573), 1694-1697. [13] Fedoroff, N. V., & Cohen, J. E. (1999). Plants and population: Is there time?. Proceedings of the National Academy of Sciences, 96(11), 5903-5907.Unicef. (2015). Progress on Sanitation and Drinking-Water: 2015 Update and MDG Assessment. World Health Organization: Geneva, Switzerland. [14] Unicef. (2015). Progress on Sanitation and Drinking-Water: 2015 Update and MDG Assessment. World Health Organization: Geneva, Switzerland.
A longer life does not have to me more time spent sick or frail if we develop the technology to address the causes of aging.

Some People Worry that Longer Lives Mean Decrepitude

Whenever the topic of increasing human lifespan is discussed, the concern is sometimes raised that a longer life would mean a life spent frail and decrepit. This is sometimes known as the Tithonus error and shows a fundamental misunderstanding of the aims of rejuvenation biotechnology.

The concern is based on the ancient Greek myth of Tithonus which might be thought of as a cautionary tale warning seekers of an eternal life of its alleged inherent dangers.

The myth of Tithonus in brief

Tithonus, the story goes, was a mere mortal who was in love with Eos, the beautiful titan of the dawn. His feelings were requited, but, unfortunately, their idyll was not destined to last. Being a titan, Eos was also a deity and thus immortal, unlike Tithonus, who one day would die of old age if not of some other cause. Eos thus turned to Zeus and asked him to make Tithonus immortal as well. Zeus granted Eos’ wish, but even this did not solve the two lovers’ problem; the father of the gods had granted Tithonus immortality, not eternal youth.

Tithonus never died, but he kept aging like any other mortal; eventually, he was so decrepit, disease-ridden, and demented that his life had become unbearable. According to some tellings of the story, the result of this everlasting aging process was that Tithonus became a cricket, begging for death to come and put an end to the prison that his immortality had become; other versions say it was Eos herself who, moved to pity for her lover’s sad fate, decided to change him into a cricket.

We can guess the lesson to be drawn from this tale: Immortality may sound appealing, but there are drawbacks that make it more of a curse than a blessing.

Can anything like this actually happen? No.

This type of concern is typically raised by people who don’t have a clear picture of rejuvenation biotechnologies and fear that an extended period of frailty and decrepitude may be what scientists are after. Thankfully, quite the opposite is true, and, in fact, Tithonus’ grim fate is physically impossible.

In the fanciful realm of gods and myths, anything goes and the impossible becomes mundane, but in the real world, neither Zeus nor anyone else could make you live forever without eliminating or obviating the aging process. This is because death is nothing but the result of a critical failure of your inner workings—if you died, it means something crucial in your body stopped functioning properly and thus triggered a cascade of failure whose ultimate consequence was your death.

In particular, in the case of death by old age, the critical failure is caused by one or several pathologies resulting from a life-long process of damage accumulation. This process is slow but insidious, and it starts speeding up considerably after middle age. Frailty, weakness, and all the notorious diseases of old age are its primary consequences and are due to the fact that accumulated damage prevents your body from functioning at its best; when the damage is extensive enough, your body cannot function at all anymore.

A longer life would not mean never-ending, increasing decrepitude

Living forever while aging forever would thus be equivalent to a human-made machine still functioning despite all of its mechanisms being eventually completely broken, which is a contradiction in terms. Another way of seeing it is imagining a house that remains a house even though you keep removing its bricks one by one.

To better illustrate this point, consider cell loss, one of the hallmarks of the aging process. In a nutshell, cell loss means that your body tissues lose their building blocks over time; normally, this loss is compensated for by cell division, but during old age, this ability is impaired and, consequently, your tissues waste away.

A longer life does not have to me more time spent sick or frail if we develop the technology to address the causes of aging.

Throughout this process, we become more fragile and sick, but as long as our tissues have enough cells to perform their job, we will stay alive, although our quality of living will be impaired. Once a tissue has lost enough cells, it can no longer perform its function, and it’s easy to see how this may lead to death—for example, if you lose too many pacemaker cells, your brain will be unable to tell your heart to beat.

More generally, in the legend Tithonus kept on living for centuries despite that he continued to age, his internal organs kept wasting away, eventually disappearing altogether, and yet somehow they still functioned! Talk about having your cake and eating it too.

So, if you are concerned that a longer life would mean never-ending, increasing decrepitude, you can heave a sigh of relief. It won’t happen because it can’t happen.

What is rejuvenation biotechnology all about, then?

A very small-scale version of Tithonus’ myth does actually take place as a consequence of geriatric medicine. Geriatric medicine focuses on treating the symptoms of age-related diseases rather than their causes, with the result of modestly improving patient health and lifespan—in other words, although with the best intentions, geriatrics does prolong the time patients spend in decrepitude.

They live a little longer because mitigating the symptoms slightly postpones the inevitable, but as age-related damage keeps accumulating, eventually the point of no return is reached. It’s a bit like trying to empty a river using a coffee mug.

Rejuvenation biotechnology proposes a different approach, intervening directly on the damage causing age-related pathologies and repairing or obviating it. For example, in the case of the aforementioned problem of cell loss, stem cell therapy could be used to periodically replenish tissues, thus preventing organ and muscle wasting.

Interventions for different types of age-related damage—such as senolytics for senescent cell clearance, enzyme replacement therapy to dispose of intracellular waste, and AGE-breaking molecules to eliminate extracellular cross-links—are currently being developed, and some are even undergoing human clinical trials.

Does living longer equal a better quality of life?

In the context of rejuvenation biotechnology, the answer would clearly be yes. The aim of rejuvenation biotechnology is neither extending frailty nor achieving a modest amelioration of an elderly patient’s health; rather, the goal is to comprehensively address age-related damage to allow people to maintain youthful levels of health for as long as they live, however long that may be. This would require rejuvenating cells, tissues, and organs so that the body functions as it did in youth. So the nightmare scenario of being trapped in a decrepit body while staying alive would not happen as the body would look and function as it did in youth.

Sounds like a much better deal than that Eos struck with Zeus for Tithonus, doesn’t it?

Blood-brain barrier

The Blood-Brain Barrier’s Role in Brain Aging

Research suggests that the degradation of the blood-brain barrier over time is a factor in the development of brain diseases.

An organ we don’t want to age

As our brains age, we experience memory loss, a decreased ability to multitask, a lower attention span, and slower information processing [1, 2]. Severe diseases can occur as a result of brain aging, genetics, and lifestyle, including various dementias and Parkinson’s [3].

Many of the diseases of brain aging involve misfolded proteins in the brain, such as amyloid beta, tau, and TDP-43 [4]. However, efforts to directly target these proteins have not been fruitful [5], and another approach might be more effective. Fortunately, the field has discovered aspects of brain aging that suggest that the degradation of the blood-brain barrier over time is another major contributor and potential causal factor [6].

A barrier that degrades over time

The blood-brain barrier is a protective shield of endothelial cells lining the brain, preventing molecules in the blood from escaping into the brain [7]. This keeps people safe from potentially neurotoxic substances, as they do not make it into the brain due to the blood-brain barrier’s selection process [8].

The blood-brain barrier has been shown to degrade with age. It loses its tight junctions [9], which are formed by tightly packed endothelial cells that block all substances that are not fat-soluble, small, or gaseous [7]. There may be vessel leakage, although studies are conflicting [9].

As a whole, this degradation tends to cause harmful substances to be allowed into the brain, including potentially neurotoxic fluids and drugs that disrupt the brain’s functions [10]. One example is an increase in the protein albumin, which begins to sneak through the blood-brain barrier as it ages. This is reported to cause inflammation through its hyperstimulative effect on glial cells [10], which causes inflammaging and thus accelerated brain aging [11].

Conclusion

It is clear that the degradation of the blood-brain barrier is linked to brain aging and neurodegeneration. However, more has yet to be done to determine its exact role. Further research should be conducted to confirm these findings and to better understand the role of the blood-brain barrier in brain aging.

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Literature

[1] The National Institute on Aging. (n.d.). How the Aging Brain Affects Thinking. National Institute on Aging. Retrieved April 29, 2021, from https://www.nia.nih.gov/health/how-aging-brain-affects-thinking

[2] Nichols, H. (2020, September 10). What happens to the brain as we age? Medical News Today. https://www.medicalnewstoday.com/articles/319185

[3] Mattson, M. P., Chan, S. L., & Duan, W. (2002). Modification of Brain Aging and Neurodegenerative Disorders by Genes, Diet, and Behavior. Physiological Reviews, 82(3), 637–672. https://doi.org/10.1152/physrev.00004.2002

[4] Elobeid, A., Libard, S., Leino, M., Popova, S. N., & Alafuzoff, I. (2016). Altered Proteins in the Aging Brain. Journal of Neuropathology & Experimental Neurology, 75(4), 316–325. https://doi.org/10.1093/jnen/nlw002

[5] Advisory Board. (2020, February 12). Crushing: Another Alzheimer’s treatment trial has failed. What’s next?

[6] Erdő, F., Denes, L., & de Lange, E. (2016). Age-associated physiological and pathological changes at the blood–brain barrier: A review. Journal of Cerebral Blood Flow & Metabolism, 37(1), 4–24. https://doi.org/10.1177/0271678×16679420

[7] The University of Queensland Australia. (2018, January 11). What is the blood-brain barrier? Queensland Brain Institute – University of Queensland. https://qbi.uq.edu.au/brain/brain-anatomy/what-blood-brain-barrier

[8] Jain, K. K. (2012, September 18). Crossing the Blood-Brain Barrier: Nanotechnology Strategies. Medscape. https://www.medscape.com/viewarticle/770396

[9] Banks, W. A., Reed, M. J., Logsdon, A. F., Rhea, E. M., & Erickson, M. A. (2021). Healthy aging and the blood–brain barrier. Nature Aging, 1(3), 243–254. https://doi.org/10.1038/s43587-021-00043-5

[10] Kaufer, D. A. F. (2021, May). Damage to a Protective Shield around the Brain May Lead to Alzheimer’s and Other Diseases. Scientific American. https://www.scientificamerican.com/article/damage-to-a-protective-shield-around-the-brain-may-lead-to-alzheimers-and-other-diseases/

[11] Franceschi, C., Garagnani, P., Parini, P., Giuliani, C., & Santoro, A. (2018). Inflammaging: a new immune–metabolic viewpoint for age-related diseases. Nature Reviews Endocrinology, 14(10), 576–590. https://doi.org/10.1038/s41574-018-0059-4