The Blog

Building a Future Free of Age-Related Disease

Elderly people road sign

The All-Party Parliamentary Group on UK Healthcare Equality

The UK All Party Parliamentary Group for Longevity (APPG) launched the Levelling Up Health initiative recently. The 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.

It is estimated that health inequality between the economically poorer north and the wealthier south of the UK costs around £13 billion (~$18 billion) per year. This can mean that people living in the most deprived areas of the UK experience chronic health conditions and age-related diseases up to 19 years sooner than those living in the most affluent areas. According to the Levelling Up Health report, 1.2 million people in the UK aged 50-64 are unemployed due to health reasons.

The APPG is working hard with the UK government and healthcare industry to close the gap in life expectancy and to promote preventative strategies to support healthy longevity. Poor health driven by bad lifestyle choices and inequality of healthcare access costs the UK a huge amount of money, damages the economy, and puts strain on the welfare state.

The APPG for Longevity launched its report, Levelling Up Health, 9th April 2021 with Rt Hon Matt Hancock MP, Secretary of State for Health and Care; Professor Chris Whitty, Chief Medical Officer; and Henry Dimbleby, leading National Food Strategy, speaking at the launch of Levelling Up Health.

What has this got to do with increasing longevity?

We welcome the fact that becoming a healthier nation is now a UK government goal along with the shift towards a healthcare system that is based on prevention rather than on simply treating the already sick. While this is only indirectly related to developing technologies that target aging, it helps to pave the way for wider acceptance of them when they arrive. Therefore, having a government and healthcare industry in the UK that is open to using these technologies as part of a prevention strategy is a positive thing.

We are likely years or even decades from gaining wide societal support for the defeat of aging itself, but initiatives like this serve as useful ways to nudge society in the right direction. If more people can be convinced that health and longevity are desirable, it will not be so hard to convince them that increased longevity or perhaps even indefinite lifespans free from age-related diseases are also a good thing. This may be a small start in that direction, but at least it is a start.

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.
Research mouse

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.

Can less oxygen be a good thing?

Cell cultures are typically maintained in conditions close to atmospheric oxygen levels, but these are much higher than the levels seen inside the body. This hyper-oxygenation has been shown to accelerate cellular senescence by increasing oxidative stress compared to physiological levels. Surprisingly, studies have shown that extreme hypoxia below physiological levels reduces senescence even further by inducing a quiescent-like state. These results have led scientists to question what mechanisms and biochemical pathways lie behind these effects, and it stands in sharp contrast to a study in humans that went viral late last year, which, paradoxically, showed similar effects through increasing oxygen instead of decreasing it.

Dr. Marco Demaria’s research team at the European Research Institute for the Biology of Ageing has recently investigated mild hypoxia alongside a drug that mimics its effects [1]. While previous studies have shown typical cell culture conditions (20% oxygenation) to increase cellular senescence and extreme hypoxia (0.2%) to reduce it, neither condition is physiologically appropriate. In this study, the authors therefore chose to study normal oxygen (normoxic) conditions (5%), which are similar to in vivo levels, and a milder hypoxia (1%) than the previous studies, which induced quiescence. After inducing senescence in several cell types in vitro, no differences in senescence levels were found between oxygen conditions by a variety of measures including SA-βgal staining and p16 and p21 expression. However, expression and secretion of multiple pro-inflammatory markers characteristic of the SASP were dramatically decreased in the hypoxic condition, suggesting that mild hypoxia may limit the most deleterious effects of cellular senescence.

Oxygenation levels vary throughout the body, a circumstance that the authors used to continue their study in vivo. In naturally aged mice, they compared the epidermal layers of the skin (1% oxygenation) to the liver (up to 7%). Senescence increased in both tissues as the animals aged, but SASP expression was much higher in the liver tissue. Similar effects were seen in the kidney medulla (1.5%) and kidney cortex (9%) of both mice and humans, with an approximately equal number of senescent cells between the two regions but a much lower SASP expression in the medulla.

Hypoxia reduces the SASP through AMPK and mTOR

Returning to their in vitro experiments, the authors then investigated HIF-1α, a factor known to sense low oxygen conditions and that regulates NF-κB, a transcriptional factor known to initiate the SASP. Surprisingly, inhibiting HIF-1α was not sufficient to raise SASP levels in hypoxic cells, suggesting that other mechanisms were at play. The authors hypothesized that this may be due to energy availability, if not hypoxia, and next turned to mTOR, a well-known molecule to longevity researchers. mTOR and its downstream effectors were highly expressed in SASP-expressing, normoxic conditions and nearly absent in the previously studied hypoxic conditions. Pharmacological activation of mTOR through various means restored NF-κB and SASP expression in cells cultured under hypoxic conditions.  Further, AMPK is known to increase in low-nutrient conditions, inhibiting mTOR activity, and was increased in hypoxic cells. Suppressing AMPK restored the SASP in hypoxic senescent cells and activating AMPK inhibited the SASP in normoxic senescent cells. Together, their results show the AMPK-mTOR pathway may be responsible for the SASP-suppressing effects of hypoxia.

Unfortunately, depriving patients of oxygen isn’t a feasible therapeutic strategy. A hyperbaric chamber can be used to mimic its effects, but this requires expensive equipment and patients to remain in an enclosed space to receive the treatment. Roxadustat is a compound that has been previously shown to mimic the effects of low oxygen levels. In normoxic conditions in vitro; it increased markers of hypoxia such as HIF-1α, did not affect senescence, and decreased mTOR, NF-κB, and the SASP. Mice were treated with doxorubicin, a potent chemotherapeutic agent, and were left to age naturally to test the effects of roxadustat in vivo. Senescent cell burden was not decreased in either group, but roxadustat suppressed mTOR signaling and the SASP by multiple measures. Importantly, roxadustat also improved grip strength, which is known to deteriorate with both chemotherapy treatment and aging.

Our findings highlight the importance of oxygen as a determinant for pro-inflammatory SASP expression and offer a potential new strategy to reduce detrimental paracrine effects of senescent cells.

Conclusion

On one hand, oxidative stress is a well-known cause of damage and accelerator of aging. On the other, it seems counterintuitive that reducing something as vital to life as oxygen could be beneficial. This study helps illuminate how low oxygen levels could be beneficial to cells. Additionally, the findings might also apply to other interventions that have been seen to reduce the SASP, including caloric restriction and exercise. Whether reducing the SASP is impactful enough to have meaningful effects in human patients without negative side effects has yet to be seen, but hypoxia mimetics such as roxadustat are certainly promising potential longevity treatments to follow.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Vliet, T.v., Varela-Eirin, M., Wang, B., Borghesan, M., Brandenburg, S.M., … & Demaria, M. (2021). Physiological hypoxia restrains the senescence-associated secretory phenotype via AMPK-mediated mTOR suppression. Molecular Cell, in press. https://doi.org/10.1016/j.molcel.2021.03.018

Astrocyte

Researchers Convert Astrocytes to Neurons in Vivo

Scientists have successfully reprogrammed astrocytes (a type of brain cell) into healthy neurons in the brains of living mice. This technique could potentially be used for replenishing the neuronal population in people suffering from brain damage and age-related cognitive decline [1].

Cellular fate is not sealed

Back in 2006, a group of scientists led by Shinya Yamanaka developed a technique for reprogramming somatic cells back into pluripotent stem cells. The technique introduces four pluripotency-associated transcription factors into the cells. This “cocktail” of four genes became known as Yamanaka factors, and its creators received a Nobel Prize.

Later, other researchers proved that similar results can be achieved by using small molecules rather than proteins [2]. Reprogramming using small molecules is much safer, since it neither triggers an immune reaction nor disrupts the cell’s proteostasis (protein balance). In recent years, several cocktails of small molecules have been formulated for various influences on cellular fate.

The potential implications of cellular reprogramming are enormous. In humans and other mammals, regeneration ability is nothing to boast about, and it is even poorer in certain organs, such as the brain; new neurons can form in the brain but only in certain regions and modest numbers. Cellular reprogramming can be used to create neurons from other types of resident brain cells, such as astrocytes. This might be a game-changer in treating age-related cognitive decline, as cognitive capacity is strongly related to neuron number and function [3].

Let there be neurons

Astrocytes, called such for their star-like shape, are brain cells tasked with various maintenance jobs. Astrocytes are so abundant that they outnumber neurons five to one. They are close relatives of neurons and share many morphological and chemical properties with them, which makes them perfect candidates for conversion into neurons, especially in vivo.

The authors of this paper had previously experimented with the small-molecule cocktail of Forskolin, ISX9, CHIR99021, and I-BET151 (FICB) to reprogram fibroblasts into functional neurons in vitro. This time, after tweaking the cocktail to increase efficiency, the researchers tried creating neurons from astrocytes in vitro and then in vivo. According to the paper, in vivo reprogramming circumvents various challenges that are typical for in vitro reprogramming and consequent transplantation – such as cell purification, long-term cell survival, and integration into the host tissue.

The experiments involved treating adult mice with the cocktail for two weeks. Upon completion of the treatment, the researchers confirmed that a considerable number of new neurons had been formed, although conversion rates varied depending on which part of the brain had been treated.

Healthy and well-connected 

It took many additional tests to confirm the success and address all the concerns. The researchers analyzed the morphology and genetic expression patterns of the newly formed cells to prove that these were indeed neurons formed from resident astrocytes. They were able to confirm that these neurons were fully functional by testing their electrophysiological properties – the ability to create and propagate electric currents in a neuron-like fashion.

Moreover, the scientists showed that the new neurons had established synaptic connections to endogenous neurons to become fully integrated and operational parts of the brain. This was achieved via a technique called retrograde tracing, which involves infecting neurons with a virus that only transmits between neurons via their synaptic connections, such as rabies or pseudorabies.

Neurons in various parts of the brain differ slightly, and these differences are functionally important. The researchers were excited to discover that CiNs (chemically induced neurons) displayed these region-specific properties. They speculate that the population of endogenous neurons might have guided the process of conversion towards region-specific phenotypes in what can be called neuronal peer pressure.

The researchers admit that many challenges remain before this intervention can become a therapy at your local clinic, including the development of a viable delivery strategy. They put their hopes in new techniques such as nanocarriers, which potentially can achieve sustained drug release after a single injection. Since neurons are notoriously long-lived, it would be interesting to know whether CiNs’ lifespan in humans is comparable to that of regular neurons.

Conclusion

This technique of creating chemically induced neurons from resident astrocytes in vivo can be a milestone in the fight against neuronal loss, a hallmark of age-related cognitive decline. While the brain, with its poor regenerative abilities, is a natural target for cellular reprogramming in vivo, we can also expect more research in other tissues that are prone to age-related degeneration.

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] Ma, Y., Xie, H., Du, X., Wang, L., Jin, X., Zhang, Q., … & Deng, H. (2021). In vivo chemical reprogramming of astrocytes into neurons. Cell discovery, 7(1), 1-13.

[2] Kim, Y., Jeong, J., & Choi, D. (2020). Small-molecule-mediated reprogramming: a silver lining for regenerative medicine. Experimental & molecular medicine, 52(2), 213-226.

[3] Avila, J., Llorens-Martín, M., Pallas-Bazarra, N., Bolós, M., Perea, J. R., Rodríguez-Matellán, A., & Hernández, F. (2017). Cognitive decline in neuronal aging and Alzheimer’s disease: role of NMDA receptors and associated proteins. Frontiers in neuroscience, 11, 626.

Epigenetic wrapping

New CRISPR Technology Allows Turning Genes Off and On Again

A new technique allows researchers to turn epigenetic methylation off and back on again, thus allowing the silencing and unsilencing of certain genes.

A CRISPR breakthrough

CRISPR/Cas9 is a well-known technology for editing the genome, but its potential for epigenetic editing had never been previously explored. With a directed CRISPR memory writer able to methylate and demethylate selected sections of the genome through single-guide RNA (sgRNA), this technology is capable of turning off and on selected, individual genes. The developers of this technique list multiple potential uses in the laboratory, including screening and cellular engineering, and the ability to control epigenetics on a per-gene basis is an enormous game-changer in biological research.

These epigenetic alterations persist as the cell divides, with even a short, transient CRISPRoff expression able to continue reliably silencing genes; over 80% of targeted genes remained silenced after 50 days.

Summary

A general approach for heritably altering gene expression has the potential to enable many discovery and therapeutic efforts. Here, we present CRISPRoff—a programmable epigenetic memory writer consisting of a single dead Cas9 fusion protein that establishes DNA methylation and repressive histone modifications. Transient CRISPRoff expression initiates highly specific DNA methylation and gene repression that is maintained through cell division and differentiation of stem cells to neurons. Pairing CRISPRoff with genome-wide screens and analysis of chromatin marks establishes rules for heritable gene silencing. We identify single guide RNAs (sgRNAs) capable of silencing the large majority of genes including those lacking canonical CpG islands (CGIs) and reveal a wide targeting window extending beyond annotated CGIs. The broad ability of CRISPRoff to initiate heritable gene silencing even outside of CGIs expands the canonical model of methylation-based silencing and enables diverse applications including genome-wide screens, multiplexed cell engineering, enhancer silencing, and mechanistic exploration of epigenetic inheritance.

Stem cells, OSKM, and epigenetic aging

Stem cells are distinguishable from other cells by their epigenetics; cell differentiation, the process by which cells become different types, is determined by the epigenetics of that particular cell. Currently, to create induced pluripotent stem cells (iPSCs) or other types of stem cells, the four Yamanaka factors, collectively known as OSKM, are used. Exposure to these four factors can reset the epigenetics of a cell back into a pluripotent state; this technology allows for the development of stem cell research and potential therapies.

However, if CRISPRoff and CRISPRon can be better perfected, precisely targeted, and reliably performed, techniques based on this technology could potentially be more effective in many cases than the Yamanaka factors; rather than relying on a cell’s own machinery to reset its epigenetics, the epigenetics could possibly be directly controlled instead.

Similarly, it could be much more potent in creating cells that are epigenetically youthful. The purpose of a partial epigenetic reset is to place cells back into a youthful state that is not entirely pluripotent; this process is difficult and requires precise timing and administration of epigenetic reset factors. Directly targeting the epigenetics involved would appear to be a much more ideal solution, but this also requires further refinement of the technology.

Conclusion

CRISPR-based epigenetic modifications are an obvious tool in the treatment for epigenetic alterations, one of the primary hallmarks of aging, but this technique is currently in its infancy. This technique is currently appropriate for cells in the laboratory, not for use in living organisms, and it would take substantial innovation and development before this or a related technique could ever be put to use in directly altering the epigenetics of existing cells in aged people.

However, if CRISPRoff and CRISPRon can precisely target the epigenetics of aging, researchers may be able to study epigenetic alterations far more precisely than the current state of the art allows.

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.
Albumin

Researchers Claim Serum Albumin Increases Mouse Lifespan

Before we begin, it should be noted that this study was published on biorxiv, a pre-print website that hosts papers prior to peer review. Therefore the data should not be regarded as conclusive or accurate until it has been subject to the peer review process and accepted for journal publication. Please keep that in mind while reading this article and also when assessing the pre-print itself.

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.

Serum albumin is a component of blood plasma in vertebrates, produced by the liver, and the most common blood protein found in mammals. Albumin maintains the oncotic pressure needed for the correct distribution of fluids between blood vessels and bodily tissues. Without the presence of albumin, the high pressure of the blood vessels would push more fluids into the tissues. Additionally, serum albumin is a plasma carrier, as it binds several hydrophobic steroid hormones, and it acts as a transport protein for hemin and fatty acids.

The study builds on the existing work of researchers such as Drs. Irina and Michael Conboy, who have demonstrated that aging includes modification of circulating blood factors, including serum albumin. Most recently, they showed that diluting aged blood rejuvenates old brains, improving cognition, reducing neuroinflammation, and spurring neurogenesis in old mice.

Researchers report increased longevity with albumin treatment

The researchers of this study hypothesized that at least some of the detrimental effects of aging are due to changes to serum albumin and the harmful reactions to it [1]. This makes total sense given that the bloodstream is essentially the internet of the body, allowing distant parts to communicate with each other and to react to the signaling factors circulating in the blood.

They proposed to test this by delivering unmodified serum albumin to middle-aged mice in order to dilute the presence of damaged albumin in the animals. In essence, their aim was to intervene against this aspect of aging by reversing the damaging responses to pro-aging signals in the blood.

It was unknown if this process might increase lifespan; as while previous experiments had consistently shown that rejuvenation of tissue and organs was possible, no lifespan studies had ever been carried out before, most likely due to the high costs of such studies.

The middle-aged mice (12 months old) were given serum albumin at 1.5 mg per gram of body weight or isometric saline every 3 weeks for the control group until the animals died naturally. A lifespan increase of 17.6% for females and 20.3% for males was reported by the researchers at the end of the study. The researchers also claimed that the appearance of animals of both sexes were better in the treated group, with glossier and thicker fur apparently being observed.

In addition to increased longevity, the researchers claimed that the treated mice also had increased grip strength and were better able to escape from a Barnes maze test.

Improvement of longevity is an eternal dream of human beings. Here we report that a single protein recombinant mouse serum albumin (rMSA) improved the lifespan and healthspan of C57BL/6N mice. The median lifespan extensions were 17.6% for female and 20.3% for male, respectively. The grip strength of rMSA-treated female and male mice increased by 29.6% and 17.4%, respectively. Meanwhile, the percentage of successful escape increased 23.0% in rMSA-treated male mice using the Barnes Maze test. The rMSA used in this study is young and almost undamaged. We define the concept “young and undamaged” to any protein without any unnecessary modifications by four parameters: intact free thiol (if any), no advanced glycation end-product, no carbonylation, and no homocysteinylation. Here “young and undamaged” rMSA is much younger and less damaged than the endogenous serum albumin from young mice at 1.5 months of age. We predict that young and undamaged proteins altogether can further improve the longevity.

Human serum albumin (HSA, UniProtKB P02768) is the most abundant protein in blood plasma with a serum half-life of about 21 days. Damages or unnecessary modifications of HSA are related to many pathological conditions and increase with age. Firstly, the single free thiol in Cys-34 residue of HSA has been proposed to account for approximately 80% of the total free thiols in plasma, whose oxidation is intimately linked with aging and age-related diseases. Secondly, in oxidative environments, carbonyls are also formed especially on the side chains of Pro, Arg, Lys and Thr residues in proteins. Elevated carbonyl levels in HSA have been found to be related to aging and varieties of diseases. Thirdly, the AGE accumulation of HSA is another important factor found to be involved in aging. It is widely reported that AGE formation impairs normal functions of albumin and can induce inflammatory responses, which is connected with aging and the progression of serious diseases. Fourthly, it has been widely reported that homocysteine (Hcy) increases with age and is associated with age-related degenerative disorders. HSA is a major target for homocysteinylation, thus it can efficiently protect other proteins from the toxicity of Hcy.

Therefore, treatment of freshly prepared recombinant serum albumin with no damages or unnecessary modifications is most likely to extend lifespan and healthspan. Here we report that young and undamaged recombinant mouse serum albumin (rMSA)-treated groups in natural aging mouse model obtained significantly extended lifespan with increased skeletal muscle strength and cognitive ability compared with saline-treated groups.

Conclusion

There has been considerable debate recently about whether experiments like this work by restoring lost beneficial factors in aged blood or by reducing harmful factors. If the study results here are to be believed, then it suggests that fresh albumin is enough to increase lifespan in mice. It may be the case that introducing fresh albumin to aged blood dilutes the pro-aging factors and perhaps even compensates for the existing potentially damaged albumin already present. However, more research is needed in order to establish this and the study should ideally be replicated independently,

In general, we are enthusiastic about interventions that seek to dilute, block, or even remove the harmful signals present in aged blood. We believe that they may potentially be the first true rejuvenation therapies to reach humans, given that the technology to do this is already available with little modification and would be relatively inexpensive to implement at scale.

If you are interested in learning why we have such optimism, take a look at last year’s interview with the Conboys. In fact, one group of biohackers in Russia was so excited about the idea that they couldn’t wait and decided to conduct their own longevity experiment on themselves. You can learn more about their biohacking experiment here.

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] Tang, J., Ju, A., Li, B., Zhang, S., Gong, Y., Ma, B., … & Luo, Y. (2021). Young and Undamaged rMSA Improves the Longevity of Mice. bioRxiv.

urine test

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 [1]. Such a biomarker can be detected from blood or urine, allowing for non-invasive testing, and experiments have shown that it plays a functional role in cellular senescence.

Slowing down to stay safe

Cellular senescence is a response to damage or stress in which cells stop dividing and undergo a range of other changes. Senescent cells also secrete a cocktail known as the senescence-associated secretory phenotype (SASP), which includes inflammatory factors such as cytokines as well as growth hormones, proteases, and other molecules. The SASP has a variety of local and systemic effects, and it is involved in both wound healing and chronic inflammation. It is known to maintain senescence in senescent cells and to signal for senescent cell clearance by the immune system.

The fact that senescent cells become more common with age led researchers to begin developing drugs to target them; these drugs are known as senolytics. In the past couple of years, some senolytic drugs have entered early clinical trials. “While the field has never been more promising, the lack of a simple biomarker to measure and track efficacy of these treatments has been a hindrance to progress,” said Judith Campisi, the study’s senior author, in a press release. “We are excited to bring this new biomarker to the field and look forward to it being used in the clinic.”

Looking at lipids

The new study began by surveying the lipids in quiescent, proliferating, and senescent human cells. To date, the SASP has been primarily studied from the perspective of its protein composition, though some lipids have also been characterized. The researchers wanted to find out if changes in lipid metabolism associated with the SASP might lead to changes in the cellular lipid profile.

They detected a striking increase in the level of a class of lipids known as oxylipins. A variety of oxylipins were more abundant, but the most elevated one proved to be the most important; this molecule is known as 1a,1b-dihomo-15-deoxy-D12,14-prostaglandin J2, or dihomo-15d-PGJ2.

In a series of experiments, the team showed that dihomo-15d-PGJ2 accumulates inside senescent cells. When the senescent cells die, they release the dihomo-15d-PGJ2, and it can then be detected in blood plasma or urine samples.

The researchers also showed that dihomo-15d-PGJ2 is specific to senescence. They treated mice with a chemical that induces senescence and then with a senolytic drug. They could detect the biomarker in blood and urine from the senescence-induced mice but not those that also received the senolytic.

Finally, the team showed that dihomo-15d-PGJ2 is not only a marker of senescence but plays an active role in promoting it. Interfering with the synthesis of dihomo-15d-PGJ2 resulted in a fraction of the cells not becoming senescent, and treating non-senescent cells with dihomo-15d-PGJ2 induced senescence. They were even able to demonstrate that this occurs via activation of the RAS pathway.

“The fact that one of these lipids ends up being a simple non-invasive biomarker for tracking the efficacy of treatments is a huge plus for those of us working to stem the ravages of age-related disease,” said Dr. Judith Campisi.

Cellular senescence is a stress or damage response that causes a permanent proliferative arrest and secretion of numerous factors with potent biological activities. This senescence-associated secretory phenotype (SASP) has been characterized largely for secreted proteins that participate in embryogenesis, wound healing, inflammation, and many age-related pathologies. By contrast, lipid components of the SASP are under-studied. We show that senescent cells activate the biosynthesis of several oxylipins that promote segments of the SASP and reinforce the proliferative arrest.

Notably, senescent cells synthesize and accumulate an unstudied intracellular prostaglandin, 1a,1b-dihomo-15-deoxy-delta-12,14-prostaglandin J2. Released 15-deoxy-delta-12,14-prostaglandin J2 is a biomarker of senolysis in culture and in vivo. This and other prostaglandin D2-related lipids promote the senescence arrest and SASP by activating RAS signaling. These data identify an important aspect of cellular senescence and a method to detect senolysis.

Conclusion

The ability to easily monitor the efficacy of senolytics will be invaluable in clinical trials. This biomarker could prove useful in senescence research more broadly by providing both a straightforward way to detect senescence and a novel molecular angle from which to investigate it. Further work on the other lipids that were elevated by senescence may uncover other players and help fill out our understanding of this complex, multi-faceted, and important process.

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] Wiley, CD, Sharma, R, Davis, SS, Lopez-Dominguez, JA, Mitchell, KP, et al. Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis. Cell Metabolism (2021), doi: 10.1016/j.cmet.2021.03.008
Biotech investment

Jim 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, to consider the most revolutionary ideas. Commonly given advice in the start-up world tells us to first look to the three F’s: family, friends, and fools.

However, if your venture is in biotech, the three F’s can’t provide nearly enough capital to get an operation off the ground. This is where angel investors, high-net-worth individuals who fund start-ups, come in. They get their namesake because often they are the only option for ideas that are really early or “out there.” Rather than convince a panel of grant reviewers or the board of a venture capital firm to fund a particular idea among a sea of other innovative but more traditional ideas, you only need to change the mind of a single angel investor or group. Today, the concept of longevity research is rapidly gaining adoption, but it wasn’t long ago that angel investors and the rare NIH grant were the only options for people fighting for increased longevity. Longevity enthusiasts are likely to know names like Peter Thiel, Dmitry Itskov, J. Craig Venter, Sergey Brin, Larry Ellison, and Jeff Bezos for their personal contributions, both as philanthropists and investors.

Among angel investors, Jim Mellon was one of the earliest adopters of longevity research. While his fortune has come from various other sectors, he founded Mann Bioinvest, published Cracking the Code, and started praising the healthy longevity strategy back in 2012. With all the progress and setbacks of the last decade, Jim remains optimistic about the field, recently claiming that the world is on the brink of three major revolutions, with increased longevity being one of them.

Companies

In biotech, Jim Mellon is most well-known for his role in Juvenescence, which is both a book he authored on biotech investment and a longevity company he co-founded. Since its initiation, Juvenescence has become an industry-leading incubator of other longevity-focused companies and has raised more than $150 million to date. Juvenescence has engaged in several initiatives, including anti-aging pharmacotherapies through partnerships with Napa Therapeutics, FoxBio, Sovien Therapeutics, and BYOMass. The company is also marketing supplements that don’t require a prescription, having recently partnered with BHB Therapeutics.

Its data science arm includes partnerships with the well-known Insilico Medicine, which has become one of the leading artificial intelligence and machine learning companies in the field of drug discovery. Similarly, Juvenescence has funded Relation Therapeutics in 2019 and Juvenomics just last year.

Lastly, Juvenescence has its hand in tissue regeneration and cell therapy approaches to healthy longevity via AgeX Therapeutics and LyGenesis. While still at the preclinical stage, LyGenesis has been perhaps the most successful tissue engineering and regenerative medicine company thus far. The two companies announced last month that they plan to negotiate a merger agreement to become a single entity. Meanwhile, Morphoceuticals, Inc. is a newly announced program taking aim at limb regeneration. On the heels of all this activity, which has occurred entirely in the last 4-5 years, Jim Mellon has suggested that Juvenescence may be eyeing an IPO in the near future.

Separately from Juvenescence, Jim Mellon also played a role as chairman of Regent Pacific during its acquisition of AI firm Deep Longevity last year. He’s also invested in Repair Biotechnologies and various other companies outside the scope of Juvenescence.

Beyond his investments, Jim Mellon has also made various donations to longevity nonprofits in recent years, including the UCL Institute of Healthy Ageing, Methuselah, and SENS, among others. In 2020, he donated £1 million to Oriel College in order to support and advance the study of Longevity Science at Oxford University, the largest donation of its kind.

Conclusion

For better or worse, high-net-worth individuals are imperative to the translation of treatments from the bench to bedside. While some media organizations make negative comments that billionaires are simply attempting to buy their own immortality without regard for anyone else’s health, these concerns are largely overblown. Overall, few people have done as much to increase human longevity as Jim Mellon. Beyond putting up his own capital, he’s also played a major role in convincing others to do the same, thereby accelerating longevity research and moving us towards a healthier future.

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.

Some people do not believe aging will be solved in their lifetime.

The “Not in my Lifetime” argument

For much of human history, living up to a ripe old age was seen as a gift from the gods, an aberration, or just the product of sheer luck. Given that up to the beginning of the twentieth century, many of us succumbed to disease at an early age, being extremely fortunate to live past the age of forty, it should be no surprise that living a long life is still considered today as something akin to winning the lottery.

Even when confronted with the galloping pace of scientific advances in human longevity, our historical sensibilities have led us to take a defeatist stance towards the subject: “Even if longevity interventions become available during my lifetime, I am already too late to take advantage of them, so why bother?”

Dismissing the science as being science fiction

Indeed, this hesitation to see human life extension as a real possibility in our lifetime, dismissing it as a dream belonging to the realms of science fiction[1] and futuristic utopias[2] is not an uncommon one, and as long as tangible rejuvenation therapies do not become available, this attitude will be validated as pragmatic.

Today, however, rejuvenation biotechnology is far from a fictional dream; it is a quickly growing field, and advances that may increase the lifespan of you and your children to well over a hundred years are already making their way to the clinic, and this is something we can no longer ignore.

Every reality begins with a dream. Only 114 years ago, the Wright brothers made the first powered flight a reality, and since then, we have taken to the skies, orbited the earth, and landed a man on the moon. What had been an impossible dream for millennia, that of human flight, has, in the span of a century, become a reality of everyday life for all of us. Today, most of us will have flown in an airplane and have ceased to see this as exceptional. It would be short-sighted to think that the same will not happen with new technologies, such as cryonics and rejuvenation.

Rising life expectancy and the arrival of rejuvenation therapies

One of the most powerful arguments for the reality of longer lifespans comes from the astounding increases in life expectancy in the last hundred years. Since the 1900’s, life expectancy has risen from about 47 years in developed countries to 79 years at birth.

Most children born in the West today are expected to live well over their 80’s, almost twice as long as they were 100 years ago, adding up to about 3 months per year! This means that for every four years we can remain healthy, we are awarded another year of life, and with the increasing pace of technologies whose aim is to mitigate, even reverse, the damages caused by aging, this gap is only getting shorter.

This, together with the introduction of genuine anti-aging therapies in clinics and an increase in the number of upcoming clinical trials for these drugs, makes a strong case for the arrival of these therapies in the near future.

In the last few years, there has been a huge surge of interest and investment in senolytics (drugs with the aim of clearing senescent cells), with companies such as Unity Biotechnology, Cleara, Oisin, Senolytic Therapeautics, and many others developing senolytics. Unity Biotechnology is currently developing UBX1325, a Bcl-xL inhibitor that targets a different pro-survival pathway that senescent cells use to evade destruction. UBX1325 is in Phase 1 trials to treat diabetic macular edema, and results are anticipated sometime during 2021.

Samumed is a biotech company developing drugs that target the Wnt signalling pathway. This pathway plays a central role in stem cell renewal and tissue regeneration. In May, 2019 Samumed launched a Phase 3 clinical program of its candidate drug lorecivivint (SM04690) for the treatment of knee osteoarthritis. The results from this Phase 3 clinical trial are expected to land in the later part of this year. If successful, lorecivivint could find broad application for treating multiple age-related conditions through the Wnt pathway.

There has also been a lot of excitement over the work of Drs. Irina and Michael Conboy who have spent over a decade exploring factors in young and old blood which spur or prevent regeneration respectively. They have conducted a number of animal studies suggesting that there are a handful of factors in aged blood which prevent tissue regeneration in older individuals and most importantly, when these factors are blocked or removed, tissue regeneration resumes as it did during youth. This suggests it may be possible to “reset” the signature of aged blood and restore it to a more youthful state. The technology to filter pro-aging factors from our blood already exists too, which means this could reach humans fairly soon.

Filtering the blood of the various problematic factors that drive aging and block tissue regeneration could be achieved using a modified version of an already approved technique known as apheresis. This is a medical procedure that involves removing whole blood from a patient and separating the blood into individual components so that one particular component can be removed. The remaining blood components then are reintroduced into the bloodstream of the patient. The Conboys have founded the startup biotech company IMYu to bring next-generation apheresis to the clinic.

Lastly, in December 2020, Gensight announced that its Phase 3 clinical trial was a success, meaning that mitochondrial gene therapy is now a reality in humans. The trial showed that the vision of those suffering from LHON, a mitochondrial condition that leads to loss of vision, could be restored somewhat through this gene therapy. This success opens the door for treating other mitochondrial diseases as well as aging itself as the mitochondria and their decline are one of the reasons we are.

This is only the tip of the iceberg. At this point, it is indeed challenging to continue to pull the wool over our eyes. Not only are these therapies likely to become available in our lifetime, but it seems that many of them will be reaching the market within the next decade.

Questioning our preconceived assumptions about what is possible

However, reflecting on the feasibility and the desirability of bringing aging under comprehensive medical control inevitably demands that we question many of our preconceived assumptions regarding what is possible, what is or isn’t good for us, and what is acceptable. Disputing what one had long thought to be true—or at least learned to accept—is never without effort or discomfort, and this is especially true when we consider that many of us still see aging as an inevitable, perhaps even necessary, fact of life. It should thus come as no surprise that one of the most common responses to the thought of robust rejuvenation is that of neglect; in other words, why should we concern ourselves with something that might come to pass only after we are long gone?

As we have noted above, the first rejuvenation therapies are certainly not centuries off; they are a couple of decades away at worst, and some, such as senolytics and DNA repair therapies, may be entering the clinic within the next ten years. Unlike people a hundred years ago, we have every reason to concern ourselves with the arrival of medical interventions to target aging, as our efforts now could significantly accelerate the pace at which these therapies will march from the laboratory to the clinic.

Our actions today have the possibility, for the first time in history, to bring a profound change to the number of people who may live long enough to benefit from rejuvenation. By acting to speed up the development of the first therapies in the coming years, we ensure that the large majority of people today are granted the opportunity to take advantage of them; conversely, our inaction will lead to a slowing down of the pace of progress, making the impossibility of robust rejuvenation a self-fulfilling prophecy.

In any case, people who label rejuvenation as a futile pursuit that will only benefit future generations should consider the fact that their children and grandchildren themselves form part and parcel of that generation, and at least they may stand a good chance to evade the ravages of time.

Even if we might not live long enough to benefit ourselves, this thought alone should make this enterprise a worthwhile one indeed. What may turn out to be woefully short-sighted, however, is dismissing rejuvenation as a possibility—or worse, opposing it!—on the grounds that we might not benefit from it personally. If we adopted this stance on climate change, for example, we would be quickly reprimanded as egotistical and lacking foresight.

One of the most common refrains about this grave global concern, in fact, is that even though people alive today might not live long enough to experience the worst effects of climate change and would consequently have little to gain from any countermeasures taken against it, preventing this catastrophe from happening should nonetheless be amongst our primary concerns, even if only to ensure the safety of future generations.

Conclusion

Ultimately, the future is not set in stone, and there is no way to know with absolute certainty whether rejuvenation technologies will arrive soon enough for us to take full advantage of them or not. However, good answers come to those who ask good questions, and maybe what we should be asking ourselves is not whether rejuvenation therapies will become available in our lifetime, but whether the possibility that they might is worth staking our bets on, and given the visible rate of progress in this field today, we would say that it absolutely is!

Despite our efforts, robust rejuvenation might still not have arrived by the time we reach old age, and the bitter taste of disappointment could be a difficult one to swallow. This is understandable. However, there’s another unpalatable dish that might be served cold to us as we prepare to meet the reaper: that of regret. If we do nothing today to speed up the pace of rejuvenation research, we risk spending our final days wondering whether we might have saved ourselves, and millions of others, years of unnecessary suffering if only we had decided to take action sooner.

However, even if regret sets in, if we do our part today, we can go peacefully in the knowledge that we’ve helped build a future free of age-related diseases for our children, grandchildren, and the generations to come. Does the belief that this is possible not make the risk of disappointment taste at least a little less bitter?

Literature

[1] Lazarus Long and the Howard families in Methuselah’s Children (1941) by Robert A. Heinlein; Anton York in Conquest of Life, Thrilling Wonder Stories (1937) by Eando.

[2] Struldbrugs in Jonathan Swift’s Gulliver’s Travels, 1726.

SenNet

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.

The NIH takes notice 

Cellular senescence has been at the forefront of longevity researchers’ minds for quite some time now, as it is one of the nine hallmarks of aging.

The prevailing theory postulates that senescent cells accumulate in our body with age and drive various harmful processes. Removing senescent cells has become a target of generously funded commercial research, causing numerous start-ups to sprout. Yet, there is still a lot we do not know about senescent cells, their diverse phenotypes, and the spatial-temporal patterns of their accumulation in the body, especially in humans.

Recently, the National Institutes of Health (NIH) has announced a major senescence-related project called Cellular Senescence Network (SenNet) and issued calls for grant applications. The SenNet program invites scientists to collaborate on its three major parts: Tissue Mapping Centers that will perform specimen collection and data analysis, Technology Development and Application Projects that will develop single-cell technologies to identify, characterize, and modify senescent cells, and, finally, an Organization and Data Coordinating Center that will serve as an organizational hub for the SenNet consortium. As described on the NIH website:

The goal of the SenNet consortium is to identify and functionally characterize the heterogeneity of senescent cells across multiple tissues in human health, disease, and lifespan at single-cell resolution. Through collaborative efforts, the consortium will generate a multimodal, multidimensional Atlas of senescent cells in various human tissues; develop innovative tools and technologies to identify and characterize senescent cells; and aggregate data across the Network into a searchable Atlas of Cellular Senescence, ensure the utility of the database, and promote collaboration through Network engagement with the research community.

The NIH further notes that “biomedical researchers still have many unanswered questions about how, when, why, and where senescent cells form” and that these cells’ “rarity and diversity make them difficult to identify and characterize in the body”. This sums up well the problems we have with studying senescent cells today.

Longevity experts agree that the initiative is very important. According to Dr. Aubrey de Grey, head of the SENS Research Foundation and a leading authority on aging, elimination of senescent cells is a key component of extending healthspan and, consequently, lifespan. “SenNet is thus of immense importance in that it gives academics the chance to develop knowledge that complements what the private sector is doing in this area,” he said.

Less than perfect

Outlooks are not all rosy, though. Dr. Leon Peshkin of the Harvard Medical School, while welcoming the initiative and recognizing its importance, has reservations. “SenNet gets right the insistence on multi-omics profiles, since, for instance, transcriptomics alone is known not to reflect senescence,” he said. “The initiative is meant to work out new markers of senescence, which is a great goal.” However, he is more skeptical about the NIH’s “insistence on starting from human material, which is extremely limiting for ethical and technical reasons.”

Peshkin, who is also a data science expert, adds: “Many realize that much better use for the money would be to first better understand what senescence means, and then make the Atlas. Premature collection of Big Data on a poorly defined class of cells is bound to muddy up the notion of senescence.”

According to Peshkin, several researchers have pointed out to NIH representatives that focusing solely or mostly on human cells might be too ambitious, given the insufficient amount of research and the difficulties involved in human-based studies. This might be the reason why, on March 26, the NIH issued a request for information on the best ways to incorporate murine studies in the initial project. “As a follow up to the human RFAs (requests for application), we would like to focus efforts on a similar and complementary goal in mice”, it said.

While these human maps are the ultimate goal, much research in biomedicine is performed in mice, and extrapolation of the findings to human health requires a detailed understanding of both the similarities and the differences between these species. Ultimately, bidirectional crosstalk between findings in human and mouse, combined with the ability to test the effects of experimental perturbation in mice, will more fully inform the role of cellular senescence in health and disease and the consequences of interventions targeting this process.

Asked if he sees any problems with the SenNet program, de Grey responds: “The main risk, as with any public funding initiative, is that it will work too hard to avoid duplication of effort with the private sector and will thus create, or to be more precise, perpetuate, a ‘valley of death’ at the early translational stage. Scientists are great at improving our understanding of nature, but it’s technologists who are great at improving our manipulation of nature, so it is vital that big initiatives like this should recognize that the really early-stage, pre-investable, yet goal-directed work needs just as much support as the curiosity-driven work that scientists are trained (and inclined) to focus on.”

In biotech investment, the “valley of death” is the gap between academic-based innovations and their commercial application, so the idea is to try to bridge that gap rather than to dedicate all the efforts and resources to fundamental science, regardless of its applicability.

An attitude shift?

For years, the longevity community has lamented what it viewed as utterly insufficient involvement of the NIH and other governmental bodies in the fight against aging. Does the SenNet initiative signal a fundamental shift in the NIH’s attitude towards aging research then?

“Not really,” said de Grey. “This is a case of one small part of aging becoming sufficiently well-defined in the eyes of the NIH’s decision-makers that it gets its own money. For several years, a number of people both inside and outside the NIH have been working to engender what really would be a fundamental shift, namely the allocation of really serious money to programs that are designed jointly by the NIA (the National Institute of Aging) and the institutes focused on age-related diseases. That, unfortunately, has never achieved critical mass.”

Peshkin strikes a more optimistic tone: “People in the NIH have told me there is a realization at the NIH that many diseases are more likely with age and we might be able to target the common cause.” He said that, despite its drawbacks, the initiative represents “a welcome shift in NIH priorities to supporting an agenda of ‘rejuvenation’, which until recently was considered controversial.”

Conclusion

The SenNet initiative is a major development that might signal a long-awaited change of paradigm in the NIH. The longevity community has been waiting for years for the NIH to put its massive weight behind the efforts to fight aging. Importantly, the authors of the initiative have demonstrated the ability to listen to the community and adapt. We will be closely following SenNet from now on.

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.

Methonine restriction and caloric restriction

It is well known among the longevity community that restricting calories leads to health benefits, and the practice of caloric restriction (CR) is something that we have discussed extensively. Methonine restriction (MR) is less well-known, and its biochemical mechanisms of action are still being investigated [1]. The mechanisms of MR and CR are related, and it has been shown that many of the positive results of CR may be replicated with an MR diet [2].

One of the key benefits of MR, as shown by a mouse model, is that it provides protection against obesity [3]. Mice on an MR diet were protected against the obesity caused by a high-fat diet and did not suffer from insulin resistance. However, the mice in that experiment suffered from low bone density due to MR.

Selenium confers MR-like effects in mice

In this study, MR was shown to increase FGF21, which has been shown to have positive effects on longevity, and decrease IGF-1, a well-known hormone that has been shown to have contradictory effects in human beings. However, these effects were surprisingly sex-specific. In male mice, FGF21 spiked strongly under an MR diet, but male mice fed a selenium-supplemented diet did not produce nearly as much of this protein. Female mice administered an MR diet showed reduced effects of FGF21, while selenium supplements were notably more effective in this regard after 8 weeks of administration. The researchers point to other data suggesting that FGF21, despite this spike, might not be the true mechanism of action for MR and MR-like interventions [4].

Most importantly, leptin and insulin concentrations, as well as total body mass, were much higher in male and female mice fed a high-fat control diet without any MR or selenium supplementation. In this respect, both MR and selenium performed very well. The researchers concur with the authors of a previous paper [5] that selenium may be an ‘insulin mimetic’, and they also suggest that there is a mechanism of action related to the mTOR pathway that is caused by depressing IGF-1.

Abstract

Methionine restriction (MR) dramatically extends the healthspan of several organisms. Methionine-restricted rodents have less age-related pathology and increased longevity as compared with controls, and recent studies suggest that humans might benefit similarly. Mechanistically, it is likely that the decreased IGF-1 signaling that results from MR underlies the benefits of this regimen. Thus, we hypothesized that interventions that decrease IGF-1 signaling would also produce MR-like healthspan benefits. Selenium supplementation inhibits IGF-1 signaling in rats and has been studied for its putative healthspan benefits. Indeed, we show that feeding mice a diet supplemented with sodium selenite results in an MR-like phenotype, marked by protection against diet-induced obesity, as well as altered plasma levels of IGF-1, FGF-21, adiponectin, and leptin. Selenomethionine supplementation results in a similar, albeit less robust response, and also extends budding yeast lifespan. Our results indicate that selenium supplementation is sufficient to produce MR-like healthspan benefits for yeast and mammals.

Conclusion

It is normal to give warnings about supplements that have been not tested in human beings for specific conditions, but such warnings are especially true for selenium, which is a micronutrient at low concentrations [6] and a well-known poison at higher concentrations. While this mouse research is promising, these selenium supplementation effects on obesity and insulin resistance may or may not apply to humans.

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Literature

[1] Latimer, M. N., Freij, K. W., Cleveland, B. M., & Biga, P. R. (2018). Physiological and molecular mechanisms of methionine restriction. Frontiers in endocrinology, 9, 217.

[2] Lee, B. C., Kaya, A., & Gladyshev, V. N. (2016). Methionine restriction and lifespan control. Annals of the New York Academy of Sciences, 1363, 116.

[3] Ables, G. P., Perrone, C. E., Orentreich, D., & Orentreich, N. (2012). Methionine-restricted C57BL/6J mice are resistant to diet-induced obesity and insulin resistance but have low bone density. PloS one, 7(12), e51357.

[4] Cooke, D., Mattocks, D., Nichenametla, S. N., Anunciado‐Koza, R. P., Koza, R. A., & Ables, G. P. (2020). Weight Loss and Concomitant Adipose Autophagy in Methionine‐Restricted Obese Mice is Not Dependent on Adiponectin or FGF21. Obesity, 28(6), 1075-1085.

[5] Stapleton, S. R. (2000). Selenium: an insulin mimetic. Cellular and Molecular Life Sciences CMLS, 57(13), 1874-1879.

[6] Zeng, H. (2009). Selenium as an essential micronutrient: roles in cell cycle and apoptosis. Molecules, 14(3), 1263-1278.

Increased Longevity and Cultural Stagnation

One concern that people have about increasing healthy human longevity is that society would become stagnant and innovation would cease as a result of people living too long. However, stagnation probably won’t happen as a result of increased longevity.

Increasing human longevity vs the status quo

Steve Jobs once said that death is life’s single best invention because it gets rid of the old and makes room for the new. This view is the core of another fairly common objection to increasing human longevity: “cultural stagnation”.

Wouldn’t all those rejuvenated people, however physically young, be always old people “inside”, and drag everyone down with them into their anachronistic, surpassed ways of thinking, making it harder for fresh ideas to take hold, ultimately hindering social progress and our growth as a species? Maybe it’d be best not to take the risk, forget increased healthy longevity, and be content with old age as it is.

Try explaining to your grandfather that the reason he has to put up with heart disease is that we’re afraid that people his age may all become troublemakers if allowed access to medical technology that might increase their healthy longevity.

Facts, please

Joking aside, this concern implies that the death of older people is somehow essential to the thriving of society, and that is one heck of a bold claim; as such, it requires extremely solid proof, because we can’t ask people to give up good health and life over someone else’s worst-case-scenario guesses.

Do we have compelling evidence that elderly people tend to be so conservative that enough of them may actually have a negative effect on social progress, or is it just a stab in the dark based on stereotypes? Are there any studies showing that people who live past a certain age inescapably become a drag on the advancement of the species, or do we say it out of a hunch? Assuming such a tendency to conservatism in the elderly, is there any proof that it’s an unavoidable consequence of chronological age that can’t be interfered with?

Until the questions above can be unequivocally answered affirmatively, the thought of forestalling this hypothetical catastrophe by opposing the development of life-saving medical biotechnology shouldn’t even cross our minds. Even then, denying medical treatments to a few who might be a hindrance to society, or not developing the treatments at all, precluding their use to everyone, doesn’t seem a very ethical way to “make room for the new”.

In any case, we can’t predict the future, so we can’t rule out any doomsday scenario with 100% accuracy. The best we can do is figuring out how much, if at all, rejuvenation biotechnology and a possible resulting increase of healthy longevity might contribute to this problem and if there wouldn’t be a way around it that doesn’t involve letting people die.

Socio-cultural contributors of stagnation

If the problem is cultural stagnation, preventing people from living too long won’t solve it. There are no guarantees that generational turnover will necessarily lead to a majority of forward-thinking people. Leaving the matter up to chance, assuming that this will create the best outcomes, is a rather simplistic and short-sighted approach to the problem.

If old people today tend to be resistant to change and stick to their ways, it’s likely because the elderly of today come from an age when knowledge wasn’t readily accessible to everyone and the stages of life were still somewhat set in stone: birth, school, work, family, retirement, death.

In this framework, it’s clearly easier for young people to think out of the box since they’re starting essentially from a clean slate and are ready to absorb new information. A lot of the knowledge that young people have access to was generally not available at all when their elders were young. On top of that, as continuous learning isn’t part of this framework, new knowledge isn’t accessible to old people even later on.

However, old people aren’t automatically closed-minded. Learning opportunities play a big role in this sense. If you maintain a healthy skepticism even about your own convictions, never stop learning, and never let your gut take your brain’s place when considering a new idea, so why would you suddenly forget all of that and become the exact opposite of yourself in your old age?

Since we’re currently living in an age of ever-increasing free access to the whole of human knowledge, and continuous learning is actively promoted as a good thing, is it reasonable to expect that the young people of today, used to this new way of life, will lose their ability to learn simply because of chronological, not biological, age?

A society is only as culturally stagnant as its members, and as long as we offer access to knowledge, their chronological age is unlikely to matter much. A society where people could enjoy increased longevity would be unlikely to change that; if anything,  this may lead to a wiser society.

Biological contributors of stagnation

Neuroplasticity is the property of the brain to form new connections between neurons, and thus ultimately the brain’s ability to reshape itself, which enables us to learn new ideas and habits and thus change our minds. As such, it is definitely a necessary condition for avoiding stagnation: if your brain can’t rewire itself, you’re going to have one heck of a hard time learning new concepts or approaches.

Younger brains are generally more plastic than older ones, and they have more pronounced neurogenesis (the ability to grow new neurons), as explained for example in this TED Talk. The talk also explains how neurogenesis and its benefits can be fostered, giving us some control over our own learning ability. However, if neuroplasticity and neurogenesis are properties of young brains, sufficiently comprehensive rejuvenation therapies might be able to restore them.

It has been shown that brain plasticity can be induced. For example, antidepressants restore neuroplasticity back to more youthful levels in the cerebral cortices of adult rats [1, 2]. This effect has been noticed even in the visual cortex [3], and it could be induced even without the use of drugs [4].

A study on senescent cell clearance showed that elderly mice whose senescent cells were regularly purged exhibited some behavioral traits typical of younger mice, such as exploring a cage as opposed to sticking to its sides most of the time [5]. It is unclear if senolytic treatment has had an effect on the mice’s brain in terms of plasticity, but this result is a cause for optimism.

We cannot yet conclude that rejuvenation biotechnology will necessarily be able to restore youthful neuroplasticity to a brain of any age, but there is evidence that manipulating brain plasticity pharmacologically is possible to an extent; future interventions might help us exceed even that.

Literature

[1] Castrén, E., & Antila, H. (2017). Neuronal plasticity and neurotrophic factors in drug responses. Molecular Psychiatry.

[2] Karpova, N. N., Pickenhagen, A., Lindholm, J., Tiraboschi, E., Kulesskaya, N., Ágústsdóttir, A., … & Hen, R. (2011). Fear erasure in mice requires synergy between antidepressant drugs and extinction training. Science, 334(6063), 1731-1734.

[3] Vetencourt, J. F. M., Sale, A., Viegi, A., Baroncelli, L., De Pasquale, R., O’Leary, O. F., … & Maffei, L. (2008). The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science, 320(5874), 385-388.

[4] Baroncelli, L., Sale, A., Viegi, A., Vetencourt, J. F. M., De Pasquale, R., Baldini, S., & Maffei, L. (2010). Experience-dependent reactivation of ocular dominance plasticity in the adult visual cortex. Experimental Neurology, 226(1), 100-109.

[5] Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., … & Khazaie, K. (2016). Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature, 530(7589), 184-189.

Some people think longer lives would cause loss of motivation

Increased Longevity and Lost Motivation

Of all the concerns and objections that I’ve bumped into as a rejuvenation advocate, saying that healthy longevity would deprive us of motivation in life is by far the most bizarre. I have a hard time believing this concern is so widespread that it needs discussing, but it sometimes comes up, so for completeness’ sake, let’s do it anyway.

The argument in a nutshell

It’s very simple: if aging were completely defeated, then there wouldn’t be a definite upper limit to the duration of our lives. Depending on your luck and our ability to minimise risks from other causes of death, in principle, you might live to the end of time, if that’s a thing. And this, according to some, would make you lose your motivation to be alive. No death, no reason to live, they say.

Is that so?

Some people think longer lives would be demotivating

The logic behind this argument is that the perceived inevitability of death puts a certain pressure on you; as the reasoning goes, you’ve only got so much time, so you’d better use it to get something done; without this pressure, you’d end up consistently postponing to tomorrow what could be done today.

Which is a needlessly complicated way of saying that interest, passion, necessity, generosity, etc, are not sufficient conditions to get people to do anything; unless you’re in a rush because your biological clock is ticking, laziness would take over.

Even accomplished scientists sometimes think this way, which is rather surprising: I would expect a scientist should love nothing more than having potentially unlimited time to dedicate to the study of what fascinates him so much; more importantly, a scientist who is truly passionate about his field should need no other motivators to get out of bed in the morning and do what he loves, let alone the spectre of limited time!

The way I see it, if you keep postponing doing something just because you don’t have to do it right now, then perhaps you’re not so into it after all. If you love it, why wait?

Sure enough, I postpone house chores even when I really shouldn’t, but I wouldn’t even dream of postponing that which I love doing, feel like doing, and can do right now.

The meaning of meaning

This argument has a few variations and forks, such as the boredom argument and the “death gives life meaning” argument. We encounter this argument periodically but it really does not wash, and the essence of our counterargument is this: meaning is not an intrinsic property, neither of life nor anything else. Meaning depends on an observer who attributes it to something.

A longer life is unlikely to be dull or demotivate someoneIt’s not an absolute, and there are no things that confer meaning to other things by default for everyone. In other words, you decide what gives your life meaning, and if it so happened that you could live a few centuries as opposed to a few decades, this wouldn’t necessarily and automatically make it meaningless.

The idea according to which you can’t properly appreciate or understand a concept or a feeling without its opposite has some merit, but it can’t be over-generalized or extended too much without leading to nonsense.

For example, it’s true that we often take for granted good things until we lose them, such as health, but this is no reason to say that we should lose good things just to remind ourselves that they’re good and that we should be appreciative of them. Would you say you can’t properly appreciate not having cancer until you’ve had cancer and ascertained that it’s no fun, and therefore you should have it at some point? Exactly. Not quite everything must be tried at least once.

Similarly, you don’t need misery to appreciate happiness. Knowing what misery is like might help you make a clearer distinction between misery and happiness, but it’s not like any unrealistically lucky people out there who’ve somehow never been miserable have necessarily never been happy either.

After all, happiness, sadness, and the lot are nothing but—and I don’t mean this in any diminishing way—the product of chemical reactions going on in your brain and more generally your body, and they don’t really need you to know what their opposite is like before they can happen. The first time you’ve felt anything in your life, you had no way of comparing that feeling to any other, but if, for example, it was misery, I’m sure it felt miserable anyway.

You don’t need the bad things in life to appreciate the good

It goes without saying that you don’t need death, or the idea that one day you’ll certainly die, to be motivated or appreciate the good things in your life. Why and how you appreciate things is none of my business, but if you asked for my opinion, I’d say you should appreciate good things because they’re good, not because one day you might not have them anymore.

There’s no reason to think that a good thing inevitably turns bad if you can enjoy it forever. Take friendship or your relationship with your dear ones. Do you value them because you’re reasonably sure that one day your friends won’t be around anymore, or do you value your friends because they’re good people?

A longer life is unlikely to be dull or lead to loss of motivation

Would you value your friendships less if you knew for a fact you would never lose your friends?

What about health? Do you think a day will ever come when you’ll be sick of being healthy—pun intended? And if you fill your life with good things, which you appreciate because they’re good regardless of how long they’ll last, is there any reason why you would need or want life to be finite?

Sure, however minuscule the odds, it might happen that one day you’ll run out of good things to fill your life with. But I’d wait for that to happen before rushing into any decisions as to how long I want to live.

The senate building.

The Senate Special Committee on Aging Needs Better Focus

The good news is that the United States Senate has a Special Committee on Aging. The bad news is that it has little to do with the actual processes of aging and has not meaningfully furthered the research necessary to develop medical treatments for aging itself.

Instead, the committee focuses its work on other issues concerning seniors, including retirement accommodations, robocall fraud, pension plans, prescription drug prices, and the aging workforce. In particular, throughout the COVID-19 pandemic, a large portion of the committee’s hearing and legislative activity has focused specifically on seniors’ safety in nursing homes and combatting loneliness due to isolation.

While these topics are worthy of attention and do indeed impact the well-being of older Americans, most of the committee’s efforts have little to do with preventing or delaying the onset of the age-related diseases and conditions that will ultimately prevent them from living full, productive lives and will eventually force them into retirement homes that rob them of their savings.

However, to the credit of the Senators sitting on the committee, members do appear to be aware of the connection between aging and disease, the lifestyle factors that impact how we age, and the looming consequences of the Silver Tsunami.

In a 2019 committee hearing titled Promoting Healthy Aging: Living Your Best Life Long Into Your Golden Years, senators and their invited witnesses used several terms and statistics familiar to those of us interested in longevity research.

Senator Susan Collins (R-ME) recognized the relationship between age and chronic disease in her opening testimony when discussing how lifestyle factors impact the longevity of older Americans, noting that “Aging with community means staying engaged, physically, socially, and cognitively. Mounting evidence indicates that this trifecta can help reduce the risk for serious age-related diseases from Alzheimer’s disease to cardiovascular conditions.”

In the same hearing, Dr. Rudolph Tanzi, professor of neurology at Harvard Medical School, testified about the connection between chronic disease and age along with the severe human and economic consequences of these conditions. He explained to the senators, “Approximately 8 in 10 older adults in the United States have a chronic disease, and 7 in 10 have two or more. Chronic diseases are the leading cause of death and disability and the leading drivers of the nation’s $3.3 trillion in annual health care costs.”

Still, despite the daunting numbers that lay before them and their apparent understanding that age is the key underlying factor in the formation of chronic diseases, the committee’s members have not prioritized advocating for additional appropriations for the department within the National Institute of Aging (NIA) that actually researches the biology of aging.

Instead, the committee’s activities mirror America’s disease-centric approach to medical treatment. This is most apparent in the members’ bipartisan efforts to increase funding specifically for Alzheimer’s research.

“I am delighted that last year, a bipartisan coalition, of which every member on this Committee is a part, worked hard to achieve a $425 million increase in federal funding for Alzheimer’s research — that was the largest increase in our nation’s history […] With our total investment at more than $2 billion for Alzheimer’s this year, we are on a strong path forward, and we are not going to turn back,” Senator Collins said in a hearing titled Alzheimer’s: New Directions in Biomedical Research and Caregiving.

The Senate Special Committee on Aging’s lack of awareness about the importance of understanding the biology of aging in order to fight disease is indeed frustrating and is also emblematic of the broader disconnect on the issue in Congress. But, the fact that a committee with members across the ideological spectrum who appear to have a genuine concern about the human and economic consequences of age-related diseases is actively holding hearings, and is introducing bipartisan legislation, should bring optimism to the longevity community.

What the committee is missing is the right information and sufficient pressure from constituents. With effective grassroots and Capitol Hill outreach, we can begin to fill this knowledge gap and persuade its members to shift their attention toward doing what is necessary to accelerate the development and federal approval of longevity drugs.

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VitaDAO

VitaDAO to Launch Longevity Biotech by Democracy

VitaDAO wants to democratize biotech

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.

Few would argue that the drug development process is efficient. Even as the technology surrounding the process gets better and cheaper, the time and expense required to develop a drug is only increasing. This phenomenon is so well-characterized it has its own term, Eroom’s Law, which can be thought of as the reverse of Moore’s Law.

However, few alternatives have been proposed, let alone attempted. Most often those alternatives just tweak one part of the process in its current form, for example, lowering regulatory barriers or utilizing AI for target discovery. However, it’s possible that a more disruptive system will be needed.

“What would insulin look like if it was collectively owned and funded by diabetics?”

This question was posed to me by Tyler Golato, Chief Scientist and co-founder of Molecule, as I interviewed him about the upcoming launch of VitaDAO. Molecule is a company in the traditional sense which aims to launch organizations which are anything but traditional.

“[VitaDAO aims to be] a membership organization with a flat organizational structure that works to support the development of longevity therapeutics, where all of the members collectively govern those decisions, govern a treasury, and govern how that treasury is distributed,” says Tyler. The last few years have seen the rise of decentralized autonomous organizations, called DAOs, which is where the name VitaDAO is derived from.

These organizations are built on blockchain technology, the same technology that Bitcoin uses. However, Bitcoin’s blockchain serves as a ledger to record transactions of Bitcoin between users. DAOs use other blockchains, most often Ethereum, to record things like voting records and membership, which are usually represented by a token specific to the DAO. As a proof-of-concept, DAOs have already been quite successful in the cryptocurrency space, with many DAOs currently valued at greater than a billion dollars each.

Decentralization reduces abuse of power

This new organizational structure has been a large part of their success. Their decentralization on the blockchain has profound effects on trust, truth, and power. In general terms, those with power are immensely incentivized to use it for their own benefit. When power is centralized, so too are the benefactors of the power holders’ decisions. An example of this played out recently in the WallStreetBets saga as Robinhood shut down trading of Gamestop stock to the benefit of hedge funds, even at the detriment of its users. However, the effects of this incentive structure can be seen in many places, including in the price of insulin.

Decentralizing on the blockchain specifically provides additional advantages. Even if the CEO of a company distributed decision making equally among all its employees, that could be nothing more than words. It can be taken back, it can be implemented in a way that is unfair, and, in the end, someone still needs to count the votes. Hard coding and recording these things on the blockchain provides an absolute truth to agree on, one which members can trust won’t be overturned. The “autonomous” aspect provides further benefits by efficiently cutting out middlemen where things can be done by software instead.

How is VitaDAO membership decided?

Anyone will be able join the DAO through a couple of different mechanisms. Basically, anyone can join us by contributing funds in which they would receive tokens or by contributing work. For example, a service provider or contract research organization could also join the DAO by providing preclinical development services, running qPCR experiments, etc. in exchange for a certain number of Vita tokens.

These tokens are then valuable because they allow members to engage in governance functions within the DAO itself. Governance functions will including things like deciding on how the treasury spends its money, what intellectual property strategy looks like, how many projects should be funded over a certain period, and how projects are evaluated. At first, the value of those tokens is based only on their power to govern the DAO. But as Tyler explains, “those tokens themselves ideally, in the long-term, also begin to reflect the value of the assets that VitaDAO has within its portfolios.”

Non-Fungible Tokens (NFTs)

The assets that will someday be potentially owned by VitaDAO also benefit from being on the blockchain. Coincidentally, the technology Molecule has been working on to bring this into reality has been making headlines recently in the world of art. NFTs represent items, whether that’s digital or real-world, on the blockchain and usually contain some type of signature to verify their authenticity.

While VitaDAO won’t be trading in fine art, it will be utilizing NFT technology to represent any intellectual property and data it owns. These NFTs can then only be moved with approval from the DAO. They also will have other interesting use cases, stemming from the fact they are programmable, that wouldn’t apply if they were owned only in the traditional sense.

The decisions before the decisions 

The most controversial time in the lifespan of a DAO is before its launch, and VitaDAO has not yet launched. A DAO cannot be created from thin air; it must be carefully set up before it can run on its own. Molecule and its team of advisors, which includes figures like Aubrey de Grey and LEAF’s own Keith Comito, have put together working groups to decide how the DAO will operate initially.

Many of these decisions can ultimately be changed later through proposals and votes by DAO members, but the way in which the DAO is initially set up will still be critical to its success. The working groups include various aspects of the project such as legal (i.e. how to link IP to NFTs), tokenomics (i.e. details on token fundraising and distribution), and governance (i.e. how to organize proposals and voting). While the launch date has not yet been set, they hope to finalize and release the starting conditions of the DAO by the third week of April, 2021.

We had the opportunity to interview Tyler Golato about VitaDAO. If you would prefer to read the interview, we have also provided a transcription of the interview at the end of this article.

Conclusions

VitaDAO will be the first of its kind, not just for Molecule, but in the history of biotech. The combination of multiple disruptive strategies (DAOs, NFTs, longevity research) provides a great deal of potential to compound on one another, but also makes it a particularly unstable endeavor. The most controversial stage of a DAO may be right before launch, but the riskiest moment is right after, when the project is officially transferred into the hands of the community.

It will be the community who ultimately determine the success of the DAO. In drug development, this requires a strong comprehension of many complex topics, not only the research, but regulatory and commercialization aspects as well. More than anything, the community will need a lot of patience and a high tolerance for failure if the history of drug development is any indication.

Undoubtedly, VitaDAO is an experiment worth conducting. There are a lot of reasons to be optimistic for VitaDAO’s success. Beyond that, the more diverse approaches taken in translating longevity research, the more likely it is one will bring treatments to the general population.

Further information

You can keep up with Tyler Golato and VitaDAO’s progress on Discord, Website, Twitter, Telegram group, Telegram announcement channel, and Medium. Whitepaper (v0.1): https://drive.google.com/drive/folders/1ua7We98enYYI7pN9FYh5pJLuxqeZaVdf

For those wishing to help get involved: https://forms.gle/TAtLc4tAhqymRJdy6

Transcript

I’m here with Tyler Golato of Molecule to talk about VitaDAO, an organization aiming to do longevity biotech by democracy. Tyler, first, it’s great to meet you, and thanks for taking the time to do this interview. How are you doing?

Great, thanks so much for having me, really appreciate the opportunity to chat with you.

So could you could you talk about your role a little bit and what that is within this new company VitaDAO?

My name is Tyler. As I mentioned, I’m the Chief Scientific Officer and co-founder of Molecule, which is a traditional company whose mission is to decentralize and democratize the drug development process. Over the past couple of years, we’ve been exploring different structures and processes, legal frameworks, and technological frameworks to try to facilitate what you can call a slightly more open source, more collaborative way of both funding and developing therapeutics, one that maybe bridges the traditional, monopolistic patent system with a more open-source future but without compromising the ability to file for intellectual property and therefore sacrificing the ability to actually effectively commercialize drugs.

Just one small point on that: there’s been a lot of movement recently in the therapeutic development space, thinking about more open source frameworks for developing drugs, things like the Open Source Pharma Consortium, for example. But one of the areas where that that space has really struggled is if you, for example, have a group of scientists develop a therapeutic in an open source way, and you have a bunch of people committing data to a GitHub repository, it becomes very difficult to incentivize the actual commercial development of that therapeutic, because you often lack the market exclusivity that would be a sufficient incentive for those things.

So, Molecule has really been trying to think about how to bridge these two different sides: the current system and a more open source system. One of the first experiments in that in that framework is this concept of VitaDAO, which is not a traditional company. It’s a decentralized, autonomous organization, which might be a term that I would imagine over the next year, people are going to be hearing a lot more of the same way a lot of people are hearing about NFTs now; two years ago, that was a super fringe technology.

The goal of VitaDAO is really to democratize access to longevity, therapeutics development and try to create new structures to unlock early-stage innovation within the context of preclinical longevity, therapeutics development, particularly which is happening at universities and is in a pre-startup stage, and figure out ways to allow members of the public, also experts, anyone with a general interest in longevity to become actively involved in supporting that therapeutic’s development, or any therapeutic’s development, in a really engaging and an active way.

So, trying to find strength within a community that collectively funds, the development of these therapeutics, and then an exchange that VitaDAO, which you can think of as a membership collective or a membership organization will own the intellectual property that’s generated by those those projects and the members of that organization with guidance from industry experts, who can they can engage by many different mechanisms, will play a strong governance role, and how that is actually commercialized, how it might be licensed, if IP is generated from it, for example. So, it’s not just an experiment; that shouldn’t be seen as the goal, but it really is a first experiment with these new structures and how they might be able to promote innovation in the preclinical development space.

So, Molecule is what people would think of as a typical centralized company but with the goal of creating decentralized companies and VitaDAO being one specific to longevity.

At the moment, Molecule is a traditional, centralized company. Our goal is to progressively decentralize over time. At the moment, it’s a relatively small operation. We do actually have a lot of people who help us from around the world, a lot of advisors, we have developers who work with us from all over the world, and there certainly are some decentralized components to our company, but at the moment, we are still quite centralized.

Yeah, it’s a really complex topic for people not familiar in this space. I tried to explain VitaDAO to my fiance earlier this week. And she has no experience in the cryptocurrency world. It was really, really hard.

This is something that we struggle with a lot at Molecule, and it’s something that I think is going to become easier over time. Because even in the past year, a lot of these concepts have become a lot more mainstream they were a few years ago, but structurally, it’s a different way of thinking about organizations, it’s a different way of thinking about things like intellectual property, both advantages and risks in this sense, there’s quite a few innovations being stacked on top of each other. That can be a strength in some cases, but it could also create a little bit of a barrier to entry in terms of maybe someone’s ability to rapidly understand what what we’re doing, I think maybe one of the easiest ways to to tell someone about it. If you want to move all of the technical jargon away into the back end, a really simple way to think about it would be that it’s a membership organization that works to support the development of longevity therapeutics, where all of the members collectively govern those decisions, govern a treasury and how that treasury is distributed with a flat organizational structure.

I think that’s a really good top-line way to explain it, but it’s built on this background in the world of cryptocurrency, and I’m sure plenty of our readers are well versed in that space, we’ll get to a little bit later, a lot of overlap between longevity and cryptocurrency. Bitcoin price is skyrocketing right now, NFTs are making headlines left and right, but if that’s all the exposure people have had, before we even get into the weeds of VitaDAO, how would you introduce longevity enthusiasts to the world of cryptocurrency?

So there’s a couple of key differentiations to make here. There’s a lot of terminology that’s thrown around interchangeably. You have things like cryptocurrency, you have things like blockchain, you have things like token economics, for example. All these things are tied together through this background of blockchain, which you can think of as at its simplest, at its most reduced, just to be a database system, that would be a really simplified way to describe it.

And then you have things like, for example, the Ethereum blockchain, where individual cells within that database become programmable through things like smart contracts, for example, and these have lots of different implications. And then beyond that, cryptocurrencies are the transactors of value within any of these databases that are exchanging information or keeping track of transactions. Cryptocurrencies are something that allow you to exchange value or send currency, for example, to somebody in a decentralized and trustless way that’s not managed through a bank or a centralized authority in some way.

The blockchain space, the cryptocurrency space is really interesting, because everyone has a slightly different conceptualization around these technologies, what their benefits are, but really, one of the things that the space has excelled in tremendously, is creating really interesting incentive structures, often through what you could call a subfield of economics, which is called token economics. Token economics, or a token in the context of the blockchain space, so the cryptocurrency space, can be thought about as a unit that can allow someone to to do something. I mean, so it could be you can have a token for governance, for example, where by interacting with a particular blockchain, and let’s say, burning a token that I’ve received, I can cast a vote, for example, or you can have tokens that represent ownership or something. NFTs are non-fungible tokens, they’re tokens that can represent a real world asset and they’re non fungible in that they’re not divisible in the same way that something like a Bitcoin is, which you can divide many, many times.

That’s really useful because it means that you can represent something that’s truly unique with that token, but so there’s this whole decentralized finance space, this whole really interesting economic engineering experiment that’s going on right now in the context of the cryptocurrency and blockchain space. There’s a lot of innovation happening that I think, at the moment is perceived to be quite superficial. And when I say superficial, I mean, if you’re not deep within that space, what you would probably look at and say is like, what is going on? Where is all this value being created? This must be a massive bubble, what is happening within? That we’re hedging against the dollar. Yeah, exactly. It’s magic internet money. To be completely fair, there’s a lot of truth to a lot of that, there are a lot of projects in the space.

I mean, there’s a lot of good projects in the space. But there’s also, because of the space that fundamentally lacks a high degree of regulation, you also have people who are invariably exploiting that. There’s a lot of hype around it, there’s a lot of people FOMOing into the space that maybe don’t necessarily understand what they’re doing. They just look at charts and they say, cool, chart goes up, I buy in, I make money. These are things that maybe are quite relevant right now and maybe served to bring people into the space.

But the real innovation that comes from this space lies in the technology and what it’s capable of unlocking. Something like a smart contract, for example, is such a profoundly powerful piece of technology, that a lot of people don’t fundamentally understand the implications of yet, especially in terms of creating things like decentralized systems where you can basically set something up to happen, and there’s a verified way that it happens. If it does go that way, it’s almost the point where you could replace lawyers, for example, and have a huge amount of automation on different processes, the way that people interact. Yeah, I don’t want to go super deep.

So is it fair to say, maybe, rather than characterize, VitaDAO, as in the cryptocurrency space, maybe a better way to put it would be in the blockchain space?

Yeah, I think that’s a better way to put it.

Some of the key benefits, I think which you touched on a little bit there, of being in this blockchain space, is cutting out the middleman. In a lot of cases, you can think of the blockchain as it’s been described to me, and my experience is very surface level, as you can kind of think of it as like a automated decentralized ledger of transactions. There’s various other benefits to having that process be on the blockchain. We’ve also mentioned decentralization a couple times, but I don’t think that term is necessarily intuitive to people who aren’t in the space. So just, we don’t spend too much time on it, but, what is decentralization? And why is that a benefit? Why is that a pro?

Yeah, so I mean, if you think about conventional company structures, conventional hierarchies, right, you typically have some centralized power. Then maybe you have, if you think about like an organizational chart, for example, you have someone at the top and then people underneath of them. If you think about the centralization, it’s having imagine, you know, all of these elements, all these individuals or nodes or servers, however, you want to think about this being connected in some way with a high level of redundancy, and no way of anyone to exploit the system, leverage it or exert more of a centralized authority or power over that organization.

I think the reason that VitaDAO, for example, is why decentralization is attractive is because we’re trying to create, really this idea of a democratic drug development process. It’s not just that blockchain, it’s not just this cool blockchain is a nice way to do this or something. It’s that the technology is actually the thing that makes that an absolute truth, right. So, it’s not like saying, cool, I’m going to set up this flat organization, and people must take my word on it, that it’s a flat organization. It’s the fact that it’s a flat organization is actually baked into the technology itself. And nobody has the ability to override that, which is a particularly interesting concept.

It’s when you get into token based voting, for example, it really, you know, it means to actually trigger a smart contract to make a decision like to distribute funds, for example, there must be a technological consensus reached by people actually interacting with a smart contract on the blockchain. So this becomes extremely powerful in preventing, let’s say bad actors or people from potentially trying to create certain power structures within an organization. But yeah, decentralization is particularly powerful in my opinion for its democratizing effect and its ability to distribute power very, very broadly. And therefore I think the thinking is around that, that if you distribute power very broadly, and if you have a really egalitarian structure, the outcomes tend to start to serve everyone better instead of just a few central people who might be leveraging their power.

Yeah, yeah, I think a really recent current event, I think, illustrated this really well, where if you followed the whole WallStreetBets saga, RobinHood is a great example of this centralized company where just power is kind of concentrated in this place, and they are actually able to shut down trading to their users, and in some cases, even sell some of the WallStreetBets users’ stocks for them without their permission, which is not something that could happen on the blockchain. But we could get really, really deep if we wanted to on that. Let’s get back to VitaDAO, specifically. So there’s actually been quite a lot of overlap between the longevity space and the blockchain, like, especially with a lot of big donations have come from some big names, such as Vitalik Buterin, who’s one of the if not the biggest name in the space, has made some donations. What do you see as some of the parallels between the two? And why do they kind of attract similar thinkers?

Yeah, I mean, I think they both represent extremely disruptive ways of thinking, I think they’re both trying to pioneer a different framework for the for the future, maybe relative to the status quo. One of the reasons that I was attracted to biogerontology, for example, was that, you know, previously, I was working in oncology and experimental therapeutics in the context of developing drugs for various cancers, pancreatic cancer, glioblastoma, and we were working on mechanisms of chemotherapy resistance.

Over time, I found that in the context of the sciences, I was becoming quite frustrated with the way that we were approaching individual disease areas. So this idea of silos, let’s treat breast cancer, let’s treat pancreatic cancer, let’s treat a single driver of mutation in the context of one cancer. But aging research and biogerontology and longevity were really attractive because of this idea. Well, how about we understand DNA damage and repair at a higher level and figure out ways to actually intervene in that process? So you could prevent all mutations, for example. I think you have a lot of dreamers in the field, you also have your transhumanist communities.

The longevity space goes from very academic to very fringy, and I love the space for that. And I think you find the same in crypto, you have your developers and your technology people and you have your dreamers, but they’re all tied together by this by this belief that there’s a better future that technology can help us engineer. And yeah, I think there’s definitely a natural overlap between between the two spaces.

I would also add, they both kind of have a bit of a chip on their shoulder and have faced a lot of resistance from the status quo that traditional finance and traditional disease-specific approaches to medicine. So like, personality wise, right, it’s a really great match between the two. But what about like in terms of actual functionality, like in general terms, what is VitaDAO and why is it complimentary? Why is longevity and the blockchain complimentary when you bring them together?

You could start a conventional biotech company, or you could start a longevity fund, for example, with a similar values and mission, in terms of its ability to create advanced preclinical stage, longevity therapeutics. What you couldn’t do with those structures is have really, really broad participation from the general public. One of the things that blockchain allows you to do, or really the the tokenomics around VitaDAO or this idea of creating this decentralized structure is that it allows you to tap in very actively to a very large community of enthusiasts of experts in the field, people who might want to get involved in the day to day governance.

One of the things from an incentive structure that decentralized communities have been really good at, I think you can see it. I mean, I don’t want to go too deep into the NFT space right now in general, but there’s a huge effect that can be gained by bringing together 2, 3, 4,000, 10,000 people around around a common cause. That is very difficult to do with a typical start-up structure or a funding structure or something like that. I think the best way to think about it is that blockchain or cryptocurrency is something that from a framework perspective, allows you to rather easily spin up a decentralized organization where you have power distributed among many different people with a common goal.

That’s the primary reason for using blockchain technology in this context. Now, there’s other reasons as well, which I think we’ll get into later if we began to talk a little bit about NFT’s and maybe the the device space. But you know, one of the things that we’ve seen over the past 20 years in the context of drug development and biopharma R&D in general, is that there’s really this innovation crisis that’s happening. Our technology for drug discovery is getting better and better. There’s a term called Eroom’s law, which is Moore’s Law backwards, it was coined by someone called Jack Scannell, who described this interesting problem around innovation.

You have, technology getting much cheaper, your ability to sequence the genome has gotten exponentially cheaper, even outpaced Moore’s Law, yet, we’re discovering less drugs and drug development is becoming more and more expensive. And we believe that part of the reason for this comes down to actually the way that both the organizational and business structures and intellectual property structures exist in drug development in a lot of cases and the incentives that exist. So VitaDAO is really this idea that, we’re not 100% sure yet, if this is a better way to develop drugs than the status quo. But it’s certainly a different way, it’s a way that really deserves to be tried, in our opinion.

It will not be without problems, I think it would be really fair for someone to say that there’s also very good reasons to have centralization, that there’s very good reasons to have leadership or clear leadership and clear decision making abilities within an organization. But we’re really excited to see how this experiment plays out. And if we’re able to really tap into a powerful community that’s able to do things that are more quickly and more agile led than the conventional biopharma space would be able to.

Yeah, you’d have a tough time arguing that the current drug development process is efficient, or that it’s been done in the best way possible, and so this is a dramatically different way to do it. The DAO, so the second half of VitaDAO, I don’t think we’ve actually defined that yet. That’s a decentralized autonomic organization. So more specifically, how does the DAO work?

Yeah, so basically, anyone can join the DAO, they can join the DAO through a couple of different mechanisms. One mechanism is by contributing funds to the DAO and receiving tokens, and those tokens allow members to engage in governance functions within the DAO itself. And a governance function could be anything from, let’s say, deciding on how the treasury, for example, spends its money in the context of VitaDAO, there’s a lot of different decisions that someone could help, you know, might engage in on things like, you know, what intellectual property strategy looks like, how many projects should be funded over a certain period, how projects are evaluated.

But basically, anyone can join us by contributing funds in which they would receive tokens or by contributing work. And so for example, another laboratory or a service provider or contract research organization, could also join the DAO by saying we will provide you with preclinical development services, we will run qPCR experiments for you or something like that, in exchange for a certain number of Vita tokens, and those tokens themselves can ideally, in the long term, begin to reflect the value of the assets that VitaDAO has within its portfolios. So, beyond just serving as purely as a utility for governance, if VitaDAO was very successful over the next 10 years, it might go on to fund 50 to 100 different projects and therefore hold within that DAO the IP around many different projects that have been funded.

And by having that that token or being a member, everything within that DAO was collectively owned by by all the members. So, it creates a very efficient way to be able to deploy capital, quickly get things done and support a common cause for which DAOs are typically used. They’ve been used for a long time in the context of creating pools to be able to develop new applications on Ethereum, for example, where a bunch of people come together, and they say “we want to bring together a huge community of developers, tap into all their skills to co-develop software together, decide how that software is governed, and all collectively benefit from the software that’s created.” They’ve also been used as investment vehicles in the context of the NFT art space. You have things like Flamingo DAO, for example, where you have a bunch of people pulling together money and now they’re using this as a fund to purchase different pieces of art. And all the members get to collectively vote on what art is purchased, when it should be sold, how it should be priced.

So it has this ability to democratize certain structures that have typically been inaccessible to a lot of people, for example, something like a fund, and also allow people to participate in those structures, without needing to have a ridiculous amount of capital at hand. If I said my goal is to make sure that new startups are created in the longevity landscape around longevity therapeutics, I’m going to go out and raise for a longevity fund or biotech fund, the amount of capital that I would need to have access to do that is really, really significant compared to what most people would be able to do.

So, being a member of a DAO is kind of like owning stock in a company, if the stock actually gave you power over the direction of that company.

That’s the fundamental difference and the thing to differentiate and where the power also lies as well. It would be any of the successes or benefits that are ultimately derived in the long run from VitaDAO are a function of the effort of its community and its members and not a manager in a centralized company, who’s maybe behaving in a different way than stockholders might want or incentivized quite differently. So, that’s a good way to think about it.

So the other key tool in VitaDAO’s toolbox that we’ve briefly skimmed on but haven’t gone in depth on would be the NFTs. These are non-fungible tokens. And these are a super hot topic right now. Well, there’s definitely a lot of hype, I won’t say too much, but there’s definitely a lot of hype right now. And if you’re just following that…

I think there’s too much. I will say there’s too much hype around it. Yeah, absolutely. I mean, it’s incredible. But yeah, it’s crazy.

Well, if you’re just following the news, what these probably seem like is tools for celebrities to sell virtual stuff to their fans, right? I’ve kind of had it described to me as a parallel to an autograph. Autographing an item to make it more special, and then sell it, which doesn’t really seem to fit with what we’ve been discussing so far with VitaDAO. So how will VitaDAO utilize NFTs?

So I mean, I think if you really didn’t look into the space at all, it could just seem like people were selling JPEGs for $7 million, and just seem like this completely crazy thing that makes absolutely no sense. I’ll touch on the art use case quickly, maybe just because I think it’s valuable for people to understand this, but what it really has to do with is ownership, right? It’s around ownership of something that has a certain scarcity or a certain rarity.

So for example, in the context of digital art, it could be thought of as something like a certificate of authenticity, but it’s something that can also be tied to really, really powerful economic mechanisms. For example, every time that NFT trades hands, for example, even in secondary markets, or from a sale that’s ongoing, there could be programmatically in the smart contract that’s linked to that NFT, a fee that’s always going back to the original creator.

It’s a way to create, I think, in its most optimistic use case, it’s a way to create really fair revenue for creators, artists and people to have some traceability and some provability around the provenance of a particular piece of work. Molecule as a company, separate from VitaDAO, has been quite deep in the NFT space for about two to three years now. And why that is, is because what NFTs allow you to do theoretically, although this hasn’t been done, in many practical use cases yet, is bringing real world assets into the blockchain space into the DeFi space and ultimately into the metaverse. And so from a very high level perspective, what that means is, if you took something like a patent on a therapeutic, and you attach that patent to an NFT, which we’re currently working with a group of lawyers to create this framework right now, to be able to attach real world intellectual property rights to NFTs, as opposed to art.

And this is obviously a maybe a less playful use case but something that we believe will have the power to not only affect the therapeutic space, but just more broadly, the intellectual property space. You could, for example, take that NFT of a patent, move it into structures like DAOs, purely from a technology perspective, and then be able to plug that patent into the decentralized finance ecosystem. You could, for example, collateralize it; you could transfer ownership very easily and digitally to another party or within the context of this DAO. You could even fractionalize ownership in it between many different people.

So from a very, very practical perspective, what the NFT is in the context of VitaDAO really allows you to do is take real world legal processes, licensing processes, assets, and be able to move them into a digital space to integrate into the same governance technology that is being used to run this DAO. So, it’s really a process of actually creating a technological way by which members of the DAO can interact with that intellectual property and make decisions around it.

So like a musician can take their song, right, and have a representation of that on the blockchain. And so that directly, rather than going through the megalith of the music industry, or you could take a patent or a data set or something like that, and represent that on the blockchain and then exchange it through this other powerful tool and use the blockchain to actually move that around.

Exactly. And so with things like data, if you attach a data set, for example, to an NFT, and there are specific technologies that allow this, you could basically say, only wallet addresses that are members of VitaDAO and have basically a connection to the VitaDAO smart contract, also have access to this particular data set that’s linked to that address. So it just allows you to create, it really allows you to bring these things into the digital realm in a way where there doesn’t need to be a centralized power that’s monitoring things like that access, for example, or the ability to monetize a certain data set. It allows us to say, yeah, you can attach this to this NFT, it can go into this structure.

Now, for example, wallet addresses that are holders of Vita tokens, and therefore members of this DAO have access to that, for example. And with patents, I think there’s a really strong use case for licensing in general with smart contracts. This is something that I think you’re going to be seeing happening a lot more – a combination of smart contracts and NFT’s. But I think people could look at something like VitaDAO, and be like, “longevity” “NFTs” and “blockchains.” It sounds really buzzy and hype-ey. But there’s, in all these cases, there’s a very specific technological use case for these technologies. And I think they’re often also quite different than what people are familiar with.

Yeah, even if even if they’re overhyped, there’s still reason for the hype.

100%, yeah.

Okay, so like the for any, even like a regular startup company, centralized company, decentralized company, in the longevity space or whatever market you’re in, the first step is fundraising, to actually get the project off the ground. So how have there been any decisions made for VitaDAO? How is this going to go?

There’s certain frameworks that are already in place in terms of how the fundraiser is actually going to be carried out. So the mechanics using Balancer liquidity bootstrapping pool, which people can look up and learn about if they’re interested, it’s a way to create a market with even potentially very low market caps and bootstrap initial liquidity into that market. It’s a tool within the decentralized finance ecosystem, people can stake into that pool and provide liquidity to it, people will also be able to through that purchase Vita tokens there.

We have initial working groups that have kicked off, looking more deeply into combining fair launch principles. Making sure that there’s not, for example, a pre sale where you pre select the people who will get to buy Vita tokens and also ensuring that the mechanics of the system and the economics of the system exist to serve the goals of the structure primarily, and not speculators and things like that. One of the key things that’s really important with tokenomics, and setting up a structure like this is doing it in such a way that it really serves the use case that you’re going for, and that it can’t be easily exploited or something like that.

So one of the things that we’re relying on is basically through the community, setting up working groups on how the tokenomics should be structured, how much we’re raising, what a single Vita token should cost, and what that confers in terms of governance rights. And all of that is still very actively ongoing but should be finalized within the next four weeks.

Yeah, that’s a huge point of the launch, right? It’s a huge point of, I would say contention in the DAO space. So it’s really good that you guys are keeping fairness top of mind for that. And presale is kind of like a big warning sign if people are looking to invest in things like these.

Exactly. I think once a DAO is set up and running and the smart contracts are in place, and the raise has gone through, it’s actually very difficult to change things or say, “oh, maybe we want to do things differently, or maybe we should have done X or Y.” Of course, members can always vote on proposals to change the way things work. But getting the launch right, the initial structure right, and the governance right is really the thing that determines if the structure is going to be viable and successful in its long-term mission. Molecule and my business partner, Paul and I, are initiators of this DAO along with several other people.

But our role will be as a service provider role to VitaDAO. We’ll be providing the framework to turn data sets and intellectual property into NFTs. We’ll also be providing a funnel to certain longevity projects through relationships that we’ve built up in the space. But, in the long term, if the DAO wanted to use a completely different service provider, they have the right to do that, and the DAO should ultimately be set up in part with the community that it’s going to be serving. There’s a lot of these questions that people have been asking me recently that I would love to have really concrete answers to, but unfortunately, a lot of the things are still very much a work in progress that’s happening through the community itself.

Yeah, I’ll just add that one of the most interesting parts of this, to me anyways, if you kind of think of VitaDAO as like a startup company, right? Startup companies are funded exclusively through venture capitalists. And there’s no way for the individual investor, the little guy, to get their foot in the door, or put up put up investment in startup companies. I think in the US, it’s actually not allowed, you have to have a certain registration in order to invest in a startup company. So the fact that VitaDAO is making this available to the little guy, I don’t know, that’s just really exciting to me.

Yeah, it’s the thing that’s also really exciting to us. And like the thing that we’ve been, I think this is going to be, this is maybe a slight tangent, but you know, part of the world that we imagine even with Molecule is what would drug drug discovery or drug development look like if the people funding and the people who actually own the intellectual property were patients themselves? What would insulin look like if it was collectively owned and funded by diabetics? How would decisions around that be made? What would access look like?

Very different if I had to guess, very differently.

Yeah. I’m from the US originally, I’m living in Europe now. I come from a very US-centric way of thinking about healthcare and the problems that exist, some of which are quite unique to the US, but I think speak very generally to the global pharmaceutical landscape. I think the prospect of having patients, the public, directly funding and directly owning and directly governing things, as vital as therapeutics is one of the concepts that has the possibility to actually change this system that is extremely rigid, extremely resistant to change has a lot of vested interests.

Maybe it doesn’t serve its core stakeholders so well. Like patients, at the end of the day, and one of the reasons I was so fascinated by the space and fascinated by decentralized structures, and the DeFi space, and all of this really providing a technical and legal framework to make that thing that you’re talking about possible. I think that’s one of the profound innovations with this. Yeah, and where I think we’re going to see over the next 10 years, as these systems come into maturity, and the hype cycle around them dies, and all of the teams that were in the space for the hype to die away, and the people who have been building for a long time, and really are fundamental believers in the technology, all those ideas start to realize.

I believe it’s really going to change the world in a lot of different ways. I think it’s an exciting time to be in this space.

I agree, and it happens in cycles, right? We’re in a boom cycle right now, and then there’s this great filter in the bust, cycle and then those kind of projects reemerge the next boom cycle as as the big winners. But, to move on, l guess the next step right after that funding is acquired is to deploy it. And we expect it’ll be deployed for longevity research which I would say at that early stage is typically viewed more as a donation rather than an investment. The people that are the members of the DAO community, should they be viewing this more as a donation, or is it more like an investment?

It’s not a donation, but it’s not an investment in the sense that you are providing capital for something that someone else is going to do with your money and you expect to get a certain return on that money. The benefit or the upside that VitaDAO can realize is a function of the efforts of its members and participation in that structure very actively, which would separate it from a conventional investment into an index or fund.

There’s someone managing your money and the decision making around your money and it sort of rests on other people to be able to derive some sort of return from that. So, it’s certainly not a donation. I don’t know if you can think about it in conventional terms as investment as we think about investments because the mechanism is really through governance, which is quite different. You have to do something actively as a member in this community which is, for example, vote on things related to governance.

You’re buying membership, more so.

You’re buying membership, exactly. But the other key thing to realize is that there’s a difference between the longevity. VitaDAO’s mission is not to just support basic research into the fundamental mechanisms of aging. It’s actually to support therapeutics development that does have a potentially commercializable angle and can generate intellectual property, which VitaDAO can then decide what to do with. They could contract out a biotech company to produce that drug. There’s many different things that they can do. But it shouldn’t be seen as a grand funding body that exists in the context of academic research.

Of course, I mean I fundamentally believe in that mission, but the goal here is to actually try to create a sustainable revenue stream for VitaDAO itself to allow that structure to continuously go on and fund other projects. So, in a perfect world where this concept was operated really smoothly and it was successful, VitaDAO, the structure itself, would go on to fund many different projects that were trying to let’s say develop pioneering technologies in the longevity space. Those could be diagnostics as well; they could be new biomarker tests, for example. VitaDAO would then hold the intellectual property generated from those projects, and those projects would be commercialized and that revenue would flow back to VitaDAO itself, and members could decide what to do with that further revenue and hopefully continue to fund additional projects.

So, in a perfect world, it would become something maybe akin to a self-sustaining organization that had the power to continuously fund and develop in the space without needing external injections of capital from philanthropists or things like that.

So it seems like there’s still a lot up in the air, right? I’ve been following the Discord closely, and you guys have been getting tons of great feedback and suggestions so far, but it seems like a lot is still to be decided up to these working groups. The decisions, basically the decisions before the decisions, right? The DAO is this decision making machine, but in order to get it running some decisions have to be made. Can you talk a little bit about the working groups and maybe what things besides the stuff we’ve already covered like what else is finalized so far?

The working groups are operating on a variety of topics. Those topics are legal, which covers for example the legal around the DAO itself, its ability to file for intellectual property and what sort of rights it has as an organization. The IP NFT framework that’s being pioneered from a legal architecture sort of perspective. There’s the tokenomics which comes down to, for example, the fundraise amount, the distribution for example, what sort of timeframe the fundraise happens over, what is it capped at, the mechanism by which people participate.

There’s another working group that is on the organization and governance rights, so working out things like what sort of rights a token holder has, what rights does somebody that joins the Discord have that is not necessarily a token holder. Do we differentiate between a general community member that wants to help out with a project but maybe doesn’t hold tokens? What is the relationship to service providers to the DAO, contractors for the DAO, how is administration handled within these organizations? How are proposals voted on? You know, we’re building a whole custom front end and back end for this that will look essentially like a web app where proposals will be voted on by members.

There’s actually a certain amount of the community that will be run by Discord, certain working groups it will be run via Discord and then actually a lot of front-end, back-end infrastructure that members will be able to interact with. So all of those components are quite far along in their in their development stage. I think we’re posting updates about the technology development on Twitter and have some information around the progress that the working groups have made, but the plan at the moment is that those should be finalized by about the third week of April with all of the final decision making in place for the launch of the organization itself and the initial fundraise.

That’s not far off.

We’re quite close, yeah. There’s basically a certain number of things that I think have been more or less decided so far, but I can’t really speak about them yet because the the working groups need to basically finalize the decisions and put pen to paper. So I just don’t want to and there still is what’s really interesting around this is i mean these working groups stimulate a really active debate between people around the right and wrong way to do this and it’s you know there’s no what’s really interesting is there’s no we’re sort of in like a frontier space there’s no reference point for this project there’s no one that’s done sort of quite the same thing so you know in a lot of cases by my very nature like if i wanted to know like what is the best way to do this? I would go and I would look at precedent and I would look at other frameworks that have been created and learn about what worked and what didn’t, but unfortunately yeah it’s sort of like [there aren’t any yet].

I hope that VitaDAO someday becomes the giants that other similar projects will stand on their shoulders because there aren’t any yet.

No, I hope so too. Yeah, I will be super I will be super excited if we make a contribution to the longevity space that is measurable and significant. If it does move things along you know from a therapeutic perspective or if it inspires other people to start similar structures with similar goals like I think in that sense it will have yeah served its purpose and be successful.

Yeah, it’s definitely an experiment worth conducting.

Yeah, I think so too.

We’re running short on time, but just very quickly, what’s the best way to follow the VitaDAO progress, if that’s all they wanted to do was just keep tabs on what’s going on?

Probably joining the announcement channel on Telegram and also our active Telegram group. I mean I would encourage people to like engage with the project ask questions to become a part of the community. If you just wanted to purely follow progress the Telegram announcement channel, the website, the Discord are fine places to do that, but yeah i would enourage things like that.

Twitter it seems like as well.

Yeah, Twitter, Telegram, and Discord are the three primary places where we’re engaging with community at the moment. If you want to have a slightly more active role and maybe participate, have conversations with us and other people in the community, and ask questions and poke holes in it and contribute intellectually to the project, I would really encourage anyone to become actively involved on Discord. That initial community that’s joining Discord now is probably going to grow into the community that seeds the initial DAO, and therefore people can have as much of a voice in this as me or anyone else, and I think that’s what’s really cool about joining this project. It’s not like supporting, it’s like cool, let’s build this together.

So, what if instead of just following, they wanted to donate their time, expertise, or skills?

We have a form if you join our Telegram or our Discord, there’s a link to a form you could fill out with of your skill set, what your background is. You could even potentially get involved in working groups, and it’s not just working groups that will basically carry on and then conclude when the DAO launches. There’s long term working groups on how, for example, we find projects.

What projects are supported?

We have people like Aubrey de Grey for example who are going to be active in these working groups and people like Keith Comito and it would be an amazing chance for you to interact with those people, see how decisions are made, and contribute intellectual capacity. And this goes super broad, if you’re a graphic designer, if you’re a developer, if you’re a solidity developer, and you want to help create the smart contracts for this, in the long term. I mean there’s there’s so many opportunities to get involved and help and I think the power is within the community. So if there’s any skill set that anyone has that they think might suit the project in some way join our Discord, get in touch, fill out the Google form, and we would love to work with you.

We will definitely make sure to include all those links. So, Tyler, on behalf of lifespan.io, thanks so much for your time and for answering all these questions and explaining this to us.

Yeah, thanks so much for your interest and for speaking to me. It’s really a pleasure; I’ve been a supporter of LEAF for a long time and a huge fan of the work that you guys do in general and the advocacy and education that you bring to the space. So it’s really a privilege to to get to speak with you.

Thank you! We’ll be in touch and following closely.

 
Rejuvenation Roundup March

Rejuvenation Roundup March 2021

It might be April Fool’s Day, but with the ongoing pandemic, age-related diseases are even less funny this year than they were last year. Let’s take a look at what people have been doing about them in March.

LEAF News

Promising to connect biotech innovators and investors, researchers and policymakers, the Longevity Leaders World Congress will occur on May 4-7. 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.

The All-Party Parliamentary Group for Longevity has a message for all our readers in the United Kingdom:

Lord Filkin, Rt Hon Damian Green MP, Richard Sloggett and Tina Woods invite you to the launch with Rt Hon Matt Hancock MP of the report, Levelling Up Health.

COVID-19 has had a devastating impact on our country, exposing our nation’s poor health and our health inequalities – 90% of those who died with Covid had significant prior poor health. A new healthcare system is essential to confront how unhealthy we are.

The report sets out why this is needed and what should be done. It proposes a 10 Year Health Improvement Plan, a new Health Improvement Fund, a shift in political attitudes that have impeded progress, clear priorities for action, and the need to challenge and change organisations that harm our children and our health.

All of society and all parties must seize the moment to improve our health; we show how.

Team and Activities

We Celebrate Our Seventh Birthday!: lifespan.io celebrated its seventh birthday this month, and we’re very thankful to all of our donors for supporting us for all these years.

David Gobel on 3D-Printed Organs at EARD2020: At last year’s Ending Age-Related Diseases 2020 conference, David Gobel of the Methuselah Foundation discussed how animal trials are insufficient in analyzing human diseases and suggested that 3D-printed organs would perform more effectively.

Panel Discussion of Media and Early Adopters at EARD2020: Keith Comito of lifespan.io, Sonia Arrison of 100 Plus Capital, Pat Graziosi of Life Noggin, Greg Grinberg of ActualFood and Life+, and Tim Maupin of Twocoats and lifespan.io discuss how mass media can be used in engaging people who are receptive to the idea of life extension.

Interviews

Matt Kaeberlein interviewThe Dog Aging Project Is Ready for Takeoff: Dr. Matt Kaeberlein talks about the development of the infrastructure to support the Dog Aging Project and its canine cohorts.

Longevity Pharmacology with Dr. João Pedro de Magalhães: Dr. de Magalhães discusses longevity pharmacology along with many other topics related to how the field of rejuvenation biotechnology is progressing.

Lifespan News

Longevity Pharmacology: Pharmaceuticals for longevity, atrophy of the circadian clock, SIRT3 and lung fibrosis, research that suggests that we should look beyond biology to slow aging, and our Science to Save the World episode on ancestral memories.

Binary Clocks: A binary clock for predicting biological age, the growing number of startups focused on aging, lifespan.io’s seventh birthday, CAR T-cell therapy against multiple myeloma, and the effects of CBD on Alzheimer’s disease.

Dog Aging: The Dog Aging Project, a drug for cognitive decline in dogs, neural proteins in the bloodstream, a human clinical trial for unexplained anemia of aging, and Alzheimer Europe’s dementia recommendations.

Rejuvenation Roundup Podcast

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

Information and Summaries

Press the reset buttonReprogramming Old Cells Young Again: Steve Hill discusses epigenetic alterations, epigenetic resets, induced pluripotency, and the four Yamanaka factors that encourage cells to return to a more youthful state.

A Summary of Creatine: Kali Carrigan explains the popular sports supplement creatine, its history, and its effects on muscle and age-related diseases.

A Summary of NAD+: NAD+ is a critical molecule in the basic metabolism of the human body, and Steve Hill explains what it is, how it is biologically derived, what systems it is involved in, and what it does.

NMN moleculeA Summary of Nicotinamide Mononucleotide: This NMN precursor might be used to increase NAD+ availability in the human body, and human safety trials have been conducted for its use.

Video Gaming as a Geroprotective Strategy: This article cites studies showing that video games may provide some level of protection against cognitive decline.

Social Issues

Elderly coupleThe Social Hallmarks of Aging: Sedeer el-Showk highlights the work of USC professor Eileen Crimmins, which suggests that social factors play a significant part in aging.

Managing Stress Responses to Slow Down Aging: This article highlights the work of Professor Elissa Epel of UCSF, which shows how our reactions to stress influence aging.

Empty walletBroadening Longevity Research to Social Factors: Terrie Moffitt explains how social sciences can play roles in explaining age-related diseases on the societal level and developing trials that adequately take social factors into account.

Advocacy

Increased Longevity and Immortal Dictators: The idea that curing age-related diseases might lead to unaging dictators is flawed for multiple reasons.

Some People Worry that Increased Lifespans Might be Boring: Boredom is caused by not having interesting things to do in your life, and increasing your lifespan will, of necessity, give you things to do.

Is Increasing Human Lifespan Unnatural?: Humans have done a lot of unnatural things in the past to extend our lifespans, including eradicating smallpox.

Research Roundup

binary clock imageBinary Clock Predicts Biological Age: Arkadi Mazin explains how this accurate, transcriptome-based clock uses a binary algorithm to smooth out noise while measuring biological age.

Reduced Nicotinamide Mononucleotide Is a New NAD+ Precursor: Reduced NMN, known as NMNH, appears to have advantages over regular NMN and NR in delivering NAD+ to cells.

Nanoparticles in bloodQuantum Dot Nanomedicine for Longevity Drugs: This kind of nanomedicine accumulates in the liver much more quickly than other drug formulations, which has both disadvantages and advantages.

Human Trial Suggests Clearing Plaques Slows Mental Decline: An anti-amyloid antibody has finally borne fruit against Alzheimer’s disease in a human trial, although it is not a cure.

The thyroid glandThyroid Organoids Created From Human Tissue: Josh Conway explains how creating thyroid organoids from human tissues may one day lead to their common use in human beings, obviating the use of artificial thyroid hormones.

MSC Extracellular Vesicles Reduce Mouse Senescence: Greg Gillispie shows how extracellular vesicles explain many of the contradictory results of previous stem cell studies.

CGI of kidneysShortened Telomeres Increase Kidney Fibrosis Rates in Mice: This study links the well-known hallmark of telomere attrition to the common disease of kidney fibrosis in a mouse model.

Stopping Colorectal Cancer From Proliferating: Proliferating cancer cells are, in many ways, still normal stem cells, and forcing them to differentiate stops them from dividing further.

Glycine and N‐acetylcysteine (GlyNAC) supplementation in older adults improves multiple biomarkers: These biomarkers include glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition.

Effects of Beta-Hydroxy-Beta-Methylbutyrate Supplementation on Elderly Body Composition and Muscle Strength: This meta-analysis shows that this supplement benefits the muscles of elderly people, particularly bedridden patients.

Neuroprotective potential of fisetin in an experimental model of spinal cord injury: The results suggested that fisetin significantly ameliorated histological aberrations such as neuronal degeneration, necrosis, and inflammatory infiltration.

Oral administration of Akkermansia muciniphila elevates systemic antiaging and anticancer metabolites: This gut bacterium has long been associated with health benefits, and this study provides a biochemical explanation as to why.

Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions: This study shows that senescent PanIN cells support tumor growth and progression. Elimination of senescent cells may be effective as preventive therapy for the progression of precancerous lesions.

Roxithromycin attenuates bleomycin-induced pulmonary fibrosis by targeting senescent cells: This study shows that RXM may be a potential clinical agent for IPF and targeting cellular senescence may be a promising treatment for progressive age-related disease.

VEGF-A165 gene therapy ameliorates blood-labyrinth barrier breakdown and hearing loss: AAV1-mediated VEGF-A165 gene therapy is a new strategy for ameliorating vascular associated hearing disorders, including common forms of age-related hearing loss.

Prevention of acquired sensorineural hearing loss in mice by in vivo Htra2 gene editing: It may be possible to ameliorate aminoglycoside-induced deafness via Htra2 gene editing, and CRISPR/Cas9 technology may be useful in the treatment of non-inherited diseases.

Exosomes derived from human stem cells enhanced the recovery of spinal cord injury: This study provides evidence that the use of hpMSC-derived exosomes may constitute a promising therapeutic strategy for the treatment of SCI.

Chitosan hydrogel-loaded MSC-derived extracellular vesicles promote skin rejuvenation: CS hydrogel-encapsulated EVs could delay the skin aging processes by ameliorating the function of aging dermal fibroblasts.

A biomarker-based biological age in UK Biobank: This study suggests that a broader, multi-system approach to the research and prevention of the diseases of aging warrants consideration.

Epigenetic wrapping

Association of decreased DNA methylation age with improved functional age: This study demonstrates the potential utility of DNA methylation clocks to assess interventional approaches to improve health in older obese adults.

Lifestyle weight-loss intervention may attenuate methylation aging: Deviation of methylation aging from chronological age might be related to body fat distribution and glycemic control and could indicate biological age, health status and the risk for premature cardiometabolic diseases.

Aging in psoriasis vulgaris: female patients are epigenetically older than healthy controls: These findings suggest a possible presence of pathophysiological processes that occur only in female psoriatic patients.

Comparison of DNA methylation clocks in Black South African men: This study concludes that it is essential to continue studying under-represented population groups to ensure methylation-derived indicators are robust and useful in all populations.

Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders: This study identifies shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms.

Winter is coming: the future of cryopreservation: This is an in-depth review of low-temperature tissue preservation techniques and looks ahead to the future of cryonics.

A shared mechanism for lifespan extension by rapamycin, acarbose, and 17α‐estradiol: These three compounds share the same fundamental biochemical pathway as other methods of mTOR-based life extension.

The “healthy worm database” reveals strengths, weaknesses and gaps of test compound-based studies: This database offers insights into the research field of studies on healthy aging based on a frequently used model organism.

Calorie restriction prevents age-related changes in the intestinal microbiota: This study suggests that CR has a major impact on the physiological status of the gastrointestinal system, maintaining it in a more youthful state

Consumption of chilies and sweet peppers is associated with lower risk of sarcopenia in older adults: This study shows that higher consumption of chilies and sweet peppers is related to a lower risk of sarcopenia in older adults.

News Nuggets

Maximon logoMaximon Launches Longevity Biotech Builder: Maximon is a Switzerland-based biotech incubator that aims to identify and develop promising biotech companies that focus on creating therapies that target the aging processes.

Bioage Launches Clinical Trial for Unexplained Anemia of Aging: BioAge, in a recent press release, has announced the start of its phase 2a clinical trial in elderly patients with unexplained anemia.

Elastrin logoKizoo Provides Seed Funding for Elastrin Therapeutics: Rejuvenation biotechnology startup founder Kizoo has provided Elastrin, a company that focuses on removing calcification from tissue, with seed funding.

David Sinclair and Peter Attia to Co-chair $200m Biotech SPAC: Big names in longevity have put together $200 million for the creation of a special purpose acquisition company meant for fostering longevity startups.

Major Health-Related Data Project Secures Funding in the UK: In the UK, the All-Party Parliamentary Group for Longevity has secured funding for its Open Life Data project, which aims to create a framework for effective and ethical collection of health-related data.

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