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Dr. Aubrey de Grey Accelerates His Estimates – Article by Steve Hill

Dr. Aubrey de Grey Accelerates His Estimates – Article by Steve Hill

Steve Hill


Editor’s Note: In this article, Mr. Steve Hill highlights a recent webinar where Dr. Aubrey de Grey, the Biogerontology Advisor of the U.S. Transhumanist Party / Transhuman Party, revised his projections for the arrival of rejuvenation treatments in a more optimistic direction. This article was originally published by the Life Extension Advocacy Foundation (LEAF).

~ Gennady Stolyarov II, Chairman, United States Transhumanist Party / Transhuman Party, April 16, 2019


On January 28, 2019, we held a webinar with the SENS Research Foundation as part of a new ongoing series of research webinars. During the webinar, we asked Dr. Aubrey de Grey how close we might be to achieving robust mouse rejuvenation (RMR) and robust human rejuvenation, and his answer was somewhat surprising.

RMR is defined as reproducibly trebling the remaining lifespan of naturally long-lived (~3 years average lifespan) mice with therapies begun when they are already two years old.

Dr. de Grey now suggests that there is a 50/50 chance of achieving robust mouse rejuvenation within 3 years from now; recent interviews and conversation reveal that he’d adjusted this figure down from 5-6 years. He has also moved his estimation of this to arrive from around 20 years to 18 years for humans.

So, what is the basis for this advance in schedule? Dr. de Grey is more optimistic about how soon we might see these technologies arrive, as the level of crosstalk between damages appears to be higher than he originally anticipated a decade ago. This means that robust mouse and human rejuvenation may be easier than he previously believed.

We also asked Dr. de Grey which of the seven damages of aging was the most challenging to address. Originally, he thought solving cancer through OncoSENS methods was the biggest challenge in ending age-related diseases. However, intriguingly, he speaks about his enthusiasm for immunotherapy and how it may potentially solve the cancer issue and negate the need for Whole-body Interdiction of Lengthening of Telomeres (WILT), which was always considered a last-resort approach to shutting down cancer.

There are two main components of the WILT approach. The first is to delete telomerase-producing genes from as many cells as possible, as human cancers lengthen telomeres through one of two available pathways, and the second is to avoid the harmful consequences of our cells no longer having telomerase by periodically transplanting fresh stem cells, which have also had their telomerase-associated genes knocked out, to replace losses.

This approach has always been considered extreme, and Dr. de Grey has always acknowledged that this was the case. However, over a decade ago when Dr. de Grey and Michael Rae originally proposed this in the book Ending Aging, immunotherapy was simply not on the radar. Now, there are alternatives to WILT that show true potential and less need for radical solutions, and it is reassuring to see that Dr. de Grey is so enthusiastic about them.

He now suggests that MitoSENS is probably the most challenging to tackle of the seven types of damage in the SENS model of aging. This is no surprise given that DNA and mtDNA damage are highly complex issues to fix.

On that note, we asked Dr. Amutha Boominathan from the MitoSENS team which mitochondrial gene was their next target after they had successfully created nuclear copies of the ATP-6 and ATP-8 genes.

MitoSENS will be launching a new fundraising campaign on Lifespan.io later this year with the aim of raising funds to progress to more of the mitochondrial genes. This time, the aim will be to move the approach to an animal model and demonstrate how it could be used to correct mitochondrial defects.

Finally, if you are interested in getting involved directly with these webinars and joining the live audience, check out the Lifespan Heroes page.

About  Steve Hill

As a scientific writer and a devoted advocate of healthy longevity technologies, Steve has provided the community with multiple educational articles, interviews and podcasts, helping the general public to better understand aging and the means to modify its dynamics. His materials can be found at H+ Magazine, Longevity reporter, Psychology Today and Singularity Weblog. He is a co-author of the book “Aging Prevention for All” – a guide for the general public exploring evidence-based means to extend healthy life (in press).

About LIFE EXTENSION ADVOCACY FOUNDATION (LEAF)

In 2014, the Life Extension Advocacy Foundation was established as a 501(c)(3) non-profit organization dedicated to promoting increased healthy human lifespan through fiscally sponsoring longevity research projects and raising awareness regarding the societal benefits of life extension. In 2015 they launched Lifespan.io, the first nonprofit crowdfunding platform focused on the biomedical research of aging.

They believe that this will enable the general public to influence the pace of research directly. To date they have successfully supported four research projects aimed at investigating different processes of aging and developing therapies to treat age-related diseases.

The LEAF team organizes educational events, takes part in different public and scientific conferences, and actively engages with the public on social media in order to help disseminate this crucial information. They initiate public dialogue aimed at regulatory improvement in the fields related to rejuvenation biotechnology.

Proposal for Chimeric Gene Therapy (v1.3.1) – Curing Trauma, Addiction, and Conditioning – Paper by Kyrtin Atreides

Proposal for Chimeric Gene Therapy (v1.3.1) – Curing Trauma, Addiction, and Conditioning – Paper by Kyrtin Atreides

Kyrtin Atreides


Editor’s Note: The U.S. Transhumanist Party has published this research paper and proposal for a practical gene therapy by member Kyrtin Atreides in order to solicit input from other researchers in the field of gene therapy as well as to provide some ideas for further directions in research and practical applications of genetic engineering. The U.S. Transhumanist Party does not itself conduct research or recommend particular medical procedures, so the publication of this paper should be seen as promoting the exploration of research paths that could one day (hopefully sooner rather than later) materialize into viable treatments for curing diseases and lengthening lifespans. 

~ Gennady Stolyarov II, Chairman, United States Transhumanist Party, April 1, 2018

Introduction:

A wise medical director once told me that 50% of those who go into the field of Psychology need psychological help themselves. I suspect that one day I’ll be able to say the same of genetic engineering.

Epigenetics control our neurochemistry, which dictates base level reactions to stimuli, and everything from a bad meal, job, relationship, or traumatic childhood event, to warzone PTSD, can trigger epigenetic changes. [1] De Bellis, M. D., & A.B., A. Z. (2014), [2] Gudsnuk, K., & Champagne, F. A. (2012), [3] Hardy, T. M., & Tollefsbol, T. O. (2011)

Over time these changes build up, and since human society is often highly unstable due to rapid and lopsided progression, the net result is cumulative damage, similar to aging, because epigenetics attempt to attune you to an environment that doesn’t change in compatible ways. [4] Bowers, E. C., & McCullough, S. D. (2017)

What this means is that in order to roll back the clock the epigenetic equation needs to be recalculated in a local space, a process which occurs with a viral knockout, or insertion of new genetic data, within a region surrounding any given gene. The basic idea is that if you alter the dimensions of the space that the epigenetic equation covers via methylation, you cause it to recalculate the ideal distribution and genetic activation for that region based on current data, rather than the trauma which previously altered it.

By causing this update to take place, the gene expression is recalculated to values which are more closely aligned with current needs and environmental factors. Previously in human history, lives were shorter and epigenetic influences served a healthy role in promoting survival, but the problem with amassing a large pile of trauma-induced epigenetic changes becomes acutely apparent as age increases.  [5] Teschendorff, A. E., West, J., & Beck, S. (2013)

Each change is based on data fixed to the point of trauma, and any alteration to that expression is glacially slow, if it occurs at all. Often times such changes break an element of neurochemistry in the sense that the change can’t naturally reverse itself once it has been made, but it can be easily reversed with minor engineering.

Different genes act like functions in code, separate blocks which can function together, but which also contain sites where new code can be placed without causing harm to the current code. In the same way the human genome also contains 8% integrated viral DNA, which makes for an ideal target for gene knock-out.  [6] (International Human Genome Sequencing Consortium, 2001; Smit, 1999)

Proposal Part 1:

What I propose is two-fold. The first step is the creation of a gene therapy which is practically viable, costing no more than $5 per person in production. The second step is testing the top gene sites active in controlling neurochemistry with both knock-out of viral DNA, and knock-in of dormant placeholder DNA, to cause recalculation to take place.

The first is easily accomplished by understanding the nature of why anything evolves in the first place, for survival. If you create a gene therapy whose survival is guaranteed it loses reason to adapt maliciously, because there is no advantage to be gained. A classic case that demonstrates a virus becoming less lethal over time is HIV, where initially it was a death sentence, but over time not only were treatments developed, the virus became less lethal, because that lethality was acting as a detriment to the purpose of survival, and it evolved in order to live longer. [7] Payne, R., Muenchhoff, M., Mann, J., Roberts, H. E., Matthews, P., Adland, E., … Goulder, P. J. R. (2014)

The myriad of bacteria, archaea, viruses, and eukaryotic microbes in our bodies that outnumber our own cells have come to a balanced state, where our bodies are the ecosystem, and as that 8% viral DNA demonstrates a virus is no different, it favors survival and a stable environment. [8] Eloe-Fadrosh, E. A., & Rasko, D. A. (2013)

I mention this because of a key factor which makes gene therapy completely impractical today, 293T cells. Having to use specialty cells for cloning a virus that isn’t replication-competent, and is often very fragile to begin with, is one monumental waste, which is built on the unfounded fear that a replication-competent virus is in and of itself a threat. As machine learning is applied to the human genome, as well as non-human genomes, the error in that line of reasoning will become increasingly apparent.

What we need is a new gene therapy, engineered for high conversion rates, such as Adeno-Associated-Virus-7 or Lentivirus, and hybridized with a more durable, low-symptom (“clinically silent”), low-transmission-potential virus, such as Epstein-Barr Virus. By making such a virus replication-competent, but also self-inactivating (EBV) and able to integrate itself as a genetic landing site capable of being periodically updated, not only is the problem of practicality and cost solved, but the speed with which new research can be tested is greatly accelerated, and the virus is rendered stable. EBV in particular is already present in roughly 95% of adults, as it has integrated with their genomes. When combined with revised best practices any risk of bad-actor genetic engineering remains a practical impossibility.

By keeping the intermediate stages of the gene therapy in a controlled environment and only releasing the end result beyond that point, the Bio-Safety risk remains functionally unchanged, as the hypothetical “bad actor” would still require the same advanced tools, knowledge, and materials to generate a harmful virus as they already do today. The key difference in Bio-Safety terms is that by allowing the field to advance, the benefits and possible means of defense against that hypothetical would move forward, while undermining the root cause of said hypotheticals. This would be roughly equivalent to creating bulletproof sleepwear before the invention of the firearm.

The end result of utilizing such a gene therapy would be a symbiotic relationship with a genetic update mechanism, where increases to lifespan and survival rates favor both parties, resulting in potential rare mutations that better serve that purpose, like a bird evolving a better beak for catching fish.

Selection of EBV to hybridize with Lentivirus would also allow for the therapy to enter dormant cycles, avoiding immune-system rejection, and reactivating when introduced to engineered updates from additional gene therapy treatments. [9] Houldcroft, C. J., & Kellam, P. (2015)

The replication-competent gene therapy can be created with either AAV-7 or Lentivirus by means of recombination during the manufacturing process. An AAV-2 or AAV-7 variant may be preferable, if not required, for the treatment of HIV-positive humans due to the risk of interaction between any Lentivirus gene therapy and the HIV virus. It is however probable that a Lentivirus/EBV chimeric gene therapy would overwrite wild HIV virus variants rather than being overwritten by them, but rigorous testing is required, which development of this therapy would also make possible. This is partly due to the far greater size, complexity, and long-term stability of EBV compared to Lentivirus. [10] Haifeng Chen. (2015)

On a side note the genetics study that led me to realize this epigenetic mechanic was in play is shown here:

[11] Welle, S., Cardillo, A., Zanche, M., & Tawil, R. (2009)

It was by examining the difference between an adult with gene knock-out applied after maturation versus one born with the modification that the mechanic of Methylation Dimensions / Dimensions of DNA was illuminated. Since this process occurs naturally as a part of viral integration, a mechanic had to evolve that could handle the recalculation. The above study also highlights that gene therapies shouldn’t be administered to individuals prior to adulthood, due to the differences in how they impact an individual prior to biological maturation, unless the need is dire, or unless the difference can be corrected upon maturation.

Another failing point of gene therapies as they exist today is that, due to the lack of replication-competence, viral titers act as a choke-point, where the virus is injected in-mass rather than gradually converting cells, massively increasing the risk of cellular toxicity and immunotoxicity. If a gene therapy was replication-competent, even an extremely low dose could achieve a high level of cellular conversion over a period of time, potentially closing in on Bayes Error, regardless of host mass. In effect, the same dose that yields positive results in a mouse could also work for a human. [12] White, M., Whittaker, R., Gándara, C., & Stoll, E. A. (2017)

Proposal Part 2:

Once the new gene therapy is complete, the ability to repair damage at the epigenetic level becomes practical, speeding up the testing process by an order of magnitude, as well as greatly reducing cost.  For the purpose of initial testing and separation of documented effects, knock-out of viral DNA and placeholder-gene knock-in will be targeted to recalculate small regions surrounding key neurochemistry controlling genes, a few of which I’ve listed below:

HTR6 – Chromosome 1 – (5-Hydroxytryptamine Receptor 6) is a Protein Coding gene.  Diseases associated with HTR6 include Acute Stress Disorder and Amnestic Disorder.

NR4A2 – Chromosome 2 – (Nuclear Receptor Subfamily 4 Group A Member 2) is a Protein Coding gene. Diseases associated with NR4A2 include Arthritis and Late-Onset Parkinson Disease. Among its related pathways are Dopaminergic Neurogenesis and Corticotropin-releasing hormone signaling pathway. GO annotations related to this gene include transcription factor activity, sequence-specific DNA binding, and protein heterodimerization activity. An important paralog of this gene is NR4A3.

HES1 – Chromosome 3 – (Hes Family BHLH Transcription Factor 1) is a Protein Coding gene. Among its related pathways are Signaling by NOTCH1 and NOTCH2 Activation and Transmission of Signal to the Nucleus. GO annotations related to this gene include transcription factor activity, sequence-specific DNA binding, and sequence-specific DNA binding. An important paralog of this gene is HES4. [13] Epigen Global Research Consortium(2015)

DRD5 – Chromosome 4 – (Dopamine Receptor D5) is a Protein Coding gene.  This receptor is expressed in neurons in the limbic regions of the brain. It has a 10-fold higher affinity for dopamine than the D1 subtype.

SLC6A3 – Chromosome 5 – (Solute Carrier Family 6 Member 3) is a Protein Coding gene. Diseases associated with SLC6A3 include Parkinsonism-Dystonia, Infantile and Nicotine Dependence, Protection Against.

DRD1 – Chromosome 5 – (Dopamine Receptor D1) is a Protein Coding gene.  Diseases associated with DRD1 include Cerebral Meningioma and Drug Addiction.

TAAR1 – Chromosome 6 – (Trace Amine Associated Receptor 1) is a Protein Coding gene. Although some trace amines have clearly defined roles as neurotransmitters in invertebrates, the extent to which they function as true neurotransmitters in vertebrates has remained speculative. Trace amines are likely to be involved in a variety of physiological functions that have yet to be fully understood.

DDC – Chromosome 7 – (Dopa Decarboxylase) is a Protein Coding gene. Among its related pathways are Dopamine metabolism and Metabolism.

CRH – Chromosome 8 – CRH (Corticotropin Releasing Hormone, aka CRF) is a Protein Coding gene. Diseases associated with CRH include Crh-Related Related Nocturnal Frontal Lobe Epilepsy, Autosomal Dominant and Autosomal Dominant Nocturnal Frontal Lobe Epilepsy. Among its related pathways are G alpha (s) signalling events and Signaling by GPCR. GO annotations related to this gene include receptor binding and neuropeptide hormone activity. [14] Sandman CA, Curran MM, Davis EP, Glynn LM, Head K, Baram TZ.(2018)

HTR7 – Chromosome 10 – (5-Hydroxytryptamine Receptor 7) is a Protein Coding gene. Diseases associated with HTR7 include Autistic Disorder and Byssinosis.

ETS1 – Chromosome 11 – (ETS Proto-Oncogene 1, Transcription Factor) is a Protein Coding gene. Among its related pathways are Photodynamic therapy-induced NF-kB survival signaling and MAPK-Erk Pathway. GO annotations related to this gene include transcription factor activity, sequence-specific DNA binding and transcription factor binding. An important paralog of this gene is ETS2.

HTR2A – Chromosome 13 – (5-Hydroxytryptamine Receptor 2A) is a Protein Coding gene. Diseases associated with HTR2A include Schizophrenia and Major Depressive Disorder and Accelerated Response to Antidepressant Drug Treatment.

SLC6A4 – Chromosome 17 – (Solute Carrier Family 6 Member 4) is a Protein Coding gene. Diseases associated with SLC6A4 include Obsessive-Compulsive Disorder and Slc6a4-Related Altered Drug Metabolism.

TCF4 – Chromosome 18 – (Transcription Factor 4) is a Protein Coding gene. Among its related pathways are Mesodermal Commitment Pathway and Regulation of Wnt-mediated beta catenin signaling and target gene transcription. GO annotations related to this gene include transcription factor activity, sequence-specific DNA binding and protein heterodimerization activity. An important paralog of this gene is TCF12.

OXT – Chromosome 20 – (Oxytocin/Neurophysin I Prepropeptide) is a Protein Coding gene. This gene encodes a precursor protein that is processed to produce oxytocin and neurophysin I. Oxytocin is a posterior pituitary hormone which is synthesized as an inactive precursor in the hypothalamus along with its carrier protein neurophysin I. Together with neurophysin, it is packaged into neurosecretory vesicles and transported axonally to the nerve endings in the neurohypophysis, where it is either stored or secreted into the bloodstream. The precursor seems to be activated while it is being transported along the axon to the posterior pituitary. This hormone contracts smooth muscle during parturition and lactation. It is also involved in cognition, tolerance, adaptation, and complex sexual and maternal behavior, as well as in the regulation of water excretion and cardiovascular functions.

AVP – Chromosome 20 – (Arginine Vasopressin) is a Protein Coding gene. Diseases associated with AVP include Diabetes Insipidus, Neurohypophyseal and Hereditary Central Diabetes Insipidus. Among its related pathways are G alpha (s) signalling events and HIV Life Cycle. GO annotations related to this gene include protein kinase activity and signal transducer activity. An important paralog of this gene is OXT.

These genes represent only a fraction of the neurochemistry control sites, but they are disproportionately represented in terms of impact due to being frequently targeted by a wide variety of damaging sources focused on addiction, conditioning, reward-behaviors, and various forms of trauma.  By changing the dimensions of a region that methylation, phosphorylation, acetylation, and histone modification have to cover the recalculation is triggered and optimized to the current environment. [15] Tuesta, L. M., & Zhang, Y. (2014), [16] Samonte FGR.(2017)

It is also worth noting that in the case of more extreme imbalances two or more gene targets would either need to be iteratively, or simultaneously, recalculated in order to reach a balanced state. By using one gene therapy, then a second on the parallel site, such as the case with OXT vs. AVP balance, you could iteratively progress towards a balanced state with less extreme gene expression levels, like turning the sides of a Rubik’s Cube. Using multiple versions of the same gene therapy, attaching to different target sites, this process could be activated simultaneously, causing the recalculation to factor in all discovered and targeted regions at once, effectively “training” the epigenetic weights of highly connected regions, instead of working iteratively where half of them are frozen at any given time. Initially this simultaneous trigger could be via standard injection, but it could also be automated a variety of ways, including using links to circadian rhythm conditions and seasonal changes, causing routine recalculation of mental and emotional health critical gene expression. [17] Neumann, ID, Landgraf R.(2012)

Since none of the genes are directly impacted, only recalculating their level of activation, risk is kept to a bare minimum, and the same approach can be repeated to yield different results by varying the conditions present as the gene therapy takes effect.  Ideal circumstances for any given outcome can be established by varying environmental factors until the result is optimized, potentially even personalized, and though this approach would be ideally suited for a laboratory environment, it could also help to establish best-practices for administering the gene therapies once they reached human trials.

Results of epigenetic recalculation could be further utilized for mathematically modeling the potential space of gene activation when coupled with environmental data from the trial facility, increasing prediction accuracy for post-therapy gene expression, as well as the subsequent benefits.

The before-versus-after comparison between fully mapped genomes could also be used in Deep Neural Network terms to generate accurate predictions for post-therapy gene activation levels and the approximate benefits of those changes. A DNN could even be modeled to map causal relationships between epigenetic activation changes in a way that has likely never been done before, allowing for many genes with currently unknown functions to be defined, opening the door to more advanced models that could map the causal and probable space of genetic engineering with far greater accuracy.

In Closing:

How long we remain mired in the Medieval times of genetic engineering is purely up to us, as a collective we can form a safety committee which agrees to create a practical gene therapy that shifts the paradigm away from monopolistic control to one where science can advance, and people can benefit from advances without waiting 20 years for approval.

The best way to win the hearts and minds of people around the world is to give them something to be grateful for, benefiting either themselves or those they love in meaningful ways. I can think of no better start down this path than curing the epigenetic effects of trauma, as virtually everyone has suffered some form of trauma in their lives, and many are needlessly crippled by it today.

Without the scars left on humanity at the epigenetic level the negative-influence house of cards collapses, along with all of the industries who prey upon it, breaking the downward spiral and moving the dial forward, from pointing towards a deeper Dystopia to a brighter future.

Transhumanism is likewise about the freedom to choose who you are, and who you become, which in the field of genetic engineering means that a practical method for genetic updates is as much a prerequisite as the computer was a prerequisite for the Internet. It would by no means remove the threat of archaic legal constructs, but it would greatly reduce their potency, taking us one step closer to being truly Transhuman.

Taking this a step further, the ability to reset the epigenetic level influence of trauma, addiction, and conditioned behaviors is also prerequisite to any major social change, as backlash comes into play when friction of the old meets new paradigms. The act of curing the effects of trauma would in this way also serve to make people more open to new ideas, since the baseline of their neurochemistry shifting would trigger subsequent recalculation going up the chain, all the way to higher order cognitive functions. This could potentially be used to shift neurochemistry into unexplored probability space, allowing for configurations that couldn’t arise naturally.

Without the practical potential there is no room for innovation, and progress stagnates behind monumental pay-gates, but the solution can be engineered today, giving innovators access to build a better tomorrow.

Humanity is but one life form among billions of ever-evolving forms of life that we know of today, and even if only 1 in 10,000 of those lifeforms were evolving in ways compatible with our genetic structure we’d be wasting 99.9999% of the potential evolutionary improvements being made by other species.  Life in the known universe is in a perpetual race to evolve, and to compete in that race in any meaningful way, increasing the survival of the species, it is necessary to take advantage of the advances that other forms of life make, the other 99.9999%+ compute power dedicated to the task of evolving into ever more advanced and resilient beings.  While humanity may not be ready to take this step any time soon, perhaps once the world is cured of trauma this will enter the realm of consideration.

If humanity is to survive, let alone thrive, in the hazards of space, genetic engineering that grants us the resilience of life forms able to survive considerable exposure to radiation, extreme temperatures, increased gravity, and even the vacuum of space, are required for us to move forward. Even survival on Earth is a moving target, and as humanity stands today, vulnerability to any number of cataclysms remains much higher than it could be. Fans of longevity research should favor the generation of a practical gene therapy most of all, because it would only take a few direct gene edits using such a therapy to significantly increase life span, granting talented scientists more years with which they could work towards overcoming challenge after challenge.

Limiting gene therapy treatment to the rarest of diseases is like limiting internet access to the most remote parts of the world, an astronomical waste, and it is time for that to change. From the more directly Transhumanist perspective, this is a step towards being free to choose who you are right down to the genetic level, accessible to everyone, a basic human right that has yet to be written, but before reaching that point humanity needs an epigenetic tabula rasa, a slate clean of trauma, conditioning, and addiction.

Kyrtin Atreides is a researcher and member of the U.S. Transhumanist Party. In his spare time over the past two years, he has conducted research into Psychoacoustics, Quantum Physics, Genetics, Language (Advancement of), Deep Learning / Artificial General Intelligence (AGI), and a variety of other branching domains, and continues to push the limits of what can be created or discovered.

For additional reading on the subject matter mentioned herein, please refer to:

Lentivirus: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2837622/

https://viralzone.expasy.org/264?outline=all_by_species

Adeno-Associated Virus: https://www.wjgnet.com/2220-3184/full/v5/i3/28.htm

https://microbewiki.kenyon.edu/index.php/Epstein-Barr_Virus

Formal Citations:

1. De Bellis, M. D., & A.B., A. Z. (2014). “The Biological Effects of Childhood Trauma.” Child and Adolescent Psychiatric Clinics of North America23(2), 185–222. http://doi.org/10.1016/j.chc.2014.01.002

2. Gudsnuk, K., & Champagne, F. A. (2012). Epigenetic Influence of Stress and the Social Environment. ILAR Journal53(3-4), 279–288. http://doi.org/10.1093/ilar.53.3-4.279

3. Hardy, T. M., & Tollefsbol, T. O. (2011). Epigenetic diet: impact on the epigenome and cancer. Epigenomics3(4), 503–518. http://doi.org/10.2217/epi.11.71

4. Bowers, E. C., & McCullough, S. D. (2017). Linking the Epigenome with Exposure Effects and Susceptibility: The Epigenetic Seed and Soil Model. Toxicological Sciences155(2), 302–314. http://doi.org/10.1093/toxsci/kfw215

5. Teschendorff, A. E., West, J., & Beck, S. (2013). Age-associated epigenetic drift: implications, and a case of epigenetic thrift? Human Molecular Genetics22(R1), R7–R15. http://doi.org/10.1093/hmg/ddt375

6. Pakorn Aiewsakun, Aris Katzourakis(2015) Endogenous viruses: Connecting recent and ancient viral evolution. Virology. 2015 May;479-480:26-37. doi: 10.1016/j.virol.2015.02.011. Epub 2015 Mar 12.

7. Payne, R., Muenchhoff, M., Mann, J., Roberts, H. E., Matthews, P., Adland, E., … Goulder, P. J. R. (2014). Impact of HLA-driven HIV adaptation on virulence in populations of high HIV seroprevalence. Proceedings of the National Academy of Sciences of the United States of America111(50), E5393–E5400. http://doi.org/10.1073/pnas.1413339111

8. Eloe-Fadrosh, E. A., & Rasko, D. A. (2013). The Human Microbiome: From Symbiosis to Pathogenesis. Annual Review of Medicine64, 145–163. http://doi.org/10.1146/annurev-med-010312-133513

9. Houldcroft, C. J., & Kellam, P. (2015). Host genetics of Epstein–Barr virus infection, latency and disease. Reviews in Medical Virology25(2), 71–84. http://doi.org/10.1002/rmv.1816

10. Haifeng Chen. (2015) Adeno-associated virus vectors for human gene therapy. Published by Baishideng Publishing Group Inc. doi: 10.5496/wjmg.v5.i3.28

11. Welle, S., Cardillo, A., Zanche, M., & Tawil, R. (2009). Skeletal muscle gene expression after myostatin knockout in mature mice Address for reprint requests and other correspondence: S. Welle, Univ. of Rochester Medical Center, 601 Elmwood Ave., Box 693, Rochester, NY 14642 (e-mail: stephen_welle@urmc.rochester.edu). Physiological Genomics38(3), 342–350. http://doi.org/10.1152/physiolgenomics.00054.2009

12. White, M., Whittaker, R., Gándara, C., & Stoll, E. A. (2017). A Guide to Approaching Regulatory Considerations for Lentiviral-Mediated Gene Therapies. Human Gene Therapy Methods28(4), 163–176. http://doi.org/10.1089/hgtb.2017.096

13. Lillycrop KA1, Costello PM2, Teh AL3, Murray RJ2, Clarke-Harris R2, Barton SJ4, Garratt ES2, Ngo S5, Sheppard AM5, Wong J3, Dogra S3, Burdge GC2, Cooper C6, Inskip HM4, Gale CR7, Gluckman PD8, Harvey NC4, Chong YS9, Yap F10, Meaney MJ11, Rifkin-Graboi A3, Holbrook JD3; Epigen Global Research Consortium, Godfrey KM12. Int J Epidemiol. 2015 Aug;44(4):1263-76. doi: 10.1093/ije/dyv052.

14. Sandman CA, Curran MM, Davis EP, Glynn LM, Head K, Baram TZ.(2018) Am J Psychiatry. 2018 Mar 2:appiajp201716121433. doi: 10.1176/appi.ajp.2017.16121433.

15. Tuesta, L. M., & Zhang, Y. (2014). Mechanisms of epigenetic memory and addiction. The EMBO Journal33(10), 1091–1103. http://doi.org/10.1002/embj.201488106

16. Samonte FGR.(2017) The Epigenetic of Dopamine Reward in Obesity and Drug Addiction: A Philippine Perspective. J Clin Epigenet. 2017, 3:2. doi: 10.21767/2472-1158.100051

17. Neumann, ID, Landgraf R.(2012) Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci. 2012 Nov;35(11):649-59. doi: 10.1016/j.tins.2012.08.004. Epub 2012 Sep 11.

DNA as the Original Blockchain – Article by Alex Lightman

DNA as the Original Blockchain – Article by Alex Lightman

Alex Lightman


I think of DNA as the original Blockchain, code for 3D printing a billion years old.

Thinking of DNA as reusable software might enable us to increase our average life span by 800%.

If you think of DNA as code and don’t get distracted by phenotypes (appearances) and remember the First Rule of Engineering is “Steal, Don’t Invent”, you can find some pretty interesting code that is almost human.

Did you know that there are big mammals that can live over 200 years? And sharks that can live 400-600 years?

Mammals are all genetically over 98% the same DNA (the biological Blockchain) as Homo sapiens sapiens (humans).

One mammal able to live over 200 years is the Bowhead whale. The Greenland shark is known to live over 400 years. Sharks are not mammals, but you would be shocked at the genetic similarity. Start here to learn more.

I think we should breed vast herds of Bowhead whales and Greenland sharks and domesticate them in Seastead Communities, and maintain multi-century interspecies communication, based on the protocols developed by my old friend John Lilly, inventor of the isolation tank.

We have already identified the genetic components of longevity, which include high resistance to cancer.

Did you know this? This is why we need Transhumanist Party candidates and elected officials: we should be talking about and focused on life expectancy and cancer resistance. Half of Americans get cancer and half of those die of cancer – over 600,000 a year!

Genetic Causes of Longevity in Bowhead Whales

It was previously believed the more cells present in an organism, the greater the chances of mutations that cause age-related diseases and cancer.

Although the bowhead whale has thousands of times more cells than other mammals, the whale has a much higher resistance to cancer and aging. In 2015, scientists from the US and UK were able to successfully map the whale’s genome.

Through comparative analysis, two alleles that could be responsible for the whale’s longevity were identified.

These two specific gene mutations linked to the Bowhead whale’s ability to live longer are the ERCC1 gene and the proliferating cell nuclear antigen (PCNA) gene. ERCC1 is linked to DNA repair as well as increased cancer resistance. PCNA is also important in DNA repair.

These mutations enable bowhead whales to better repair DNA damage, allowing for greater resistance to cancer.

The whale’s genome may also reveal physiological adaptations such as having low metabolic rates compared to other mammals.

Changes in the gene UCP1, a gene involved in thermoregulation, can explain differences in the metabolic rates in cells.

Alex Lightman, Campaign Director for the California Transhumanist Party, has 25 years of management and social innovation experience and 15 years of chairman and chief executive experience. He is an award-winning inventor with multiple U.S. patents issued or pending and author of over one million published words, including the first book on 4G wireless, and over 150 articles in major publications. He chaired and organized 17 international conferences with engineers, scientists, and government officials since 2002, with the intention of achieving policy breakthroughs related to innovation. He is a world-class innovator and recipient of the first Economist magazine Readers’ Choice Award for “The Innovation that will Most Radically Change the World over the Decade 2010 to 2020” (awarded Oct. 21, 2010, out of 4,000 initial suggestions and votes over 5 months from 200 countries, and from 32 judges). He is the recipient of the 2nd Reader’s Award (the posthumous recipient announced 10/21/2011 was Steve Jobs). He is also the winner of the only SGI Internet 3D contest (both Entertainment and Grand Prize) out of 800 contestants.

Social innovation work includes repeatedly putting almost unknown technologies and innovation-accelerating policies that can leverage the abilities of humanity into the mainstream of media, business, government, foundations, and standards bodies, including virtual reality, augmented reality, Internet Protocol version 6, and 4G wireless broadband, open spectrum, technology transfer to developing countries, unified standards, crowd-sourcing, and collective intelligence, via over 40 US government agencies, over 40 national governments, and via international entities including the United Nations and the North Atlantic Treaty Organization (NATO).

Political credentials include a national innovation plan entitled “The Acceleration of American Innovation” for the White House Office of Science and Technology Policy, work for U.S. Senator Paul E. Tsongas (D-MA) and on several state campaigns and U.S. presidential campaigns for Democratic candidates (Gary Hart, Richard Gephardt), presentations to the United Nations, and advisory services to the governments of Bahrain, United Arab Emirates, New Zealand, Australia, Philippines, Japan, China, Korea, and India, as well as to the U.S. Congress, the White House (via the Office of Management and Budget), the U.S. Joint Chiefs of Staff, the Defense Information Systems Agency, and the North Atlantic Treaty Organization (NATO). Mr. Lightman is trained as an engineer at MIT and as a prospective diplomat and policy analyst at Harvard’s Kennedy School of Government.

SENS: Progress in the Fight Against Age-Related Diseases – Article by Nicola Bagalà and Steve Hill

SENS: Progress in the Fight Against Age-Related Diseases – Article by Nicola Bagalà and Steve Hill

Nicola Bagalà

Steve Hill


Editor’s Note: In this article, Mr. Nicola Bagalà and Steve Hill discuss the progress that the SENS Research Foundation has made in tackling the aging processes. Below is a brief summary of some of the highlights of their research efforts.  This article was originally published by the Life Extension Advocacy Foundation (LEAF).

                   ~ Kenneth Alum, Director of  Publication, U.S. Transhumanist Party, December 8, 2017

 

 

Today, there are many drugs and therapies that we take for granted. However, we should not forget that what is common and easily accessible today didn’t just magically appear out of thin air; rather, at some point, it used to be an unclear subject of study on which “more research was needed”, and even earlier, it was just a conjecture in some researcher’s head.

Hopefully, one day not too far into the future, rejuvenation biotechnologies will be as normal and widespread as aspirin is today, but right now, we’re in the R&D phase, so we should be patient and remind ourselves that the fact that we can’t rejuvenate people today doesn’t mean that nothing is being done or has been achieved to that end. On the contrary, we are witnessing exciting progress in basic research—the fundamental building blocks without which rejuvenation, or any new technology at all, would stay a conjecture.

In particular, SENS Research Foundation (SRF), a pioneering organization of the field, is sometimes unjustly accused by skeptics for failing to produce results. But produce results it has, and many at that. Skeptics either decide to ignore them or do not have access to reliable sources. For the benefit of the latter, we’ll discuss below what has been achieved by SRF over the past few years, in relation to the infamous “seven deadly things”, the seven categories of damage that aging causes as described in the SENS repair approach.

Mitochondrial mutations

In a nutshell, a mitochondrion is a cell component that is in charge of converting food nutrients into ATP (adenosine triphosphate), a chemical that powers cellular function. Your DNA is contained within the nucleus of each of your cells, but this isn’t the only DNA in your body; mitochondria have their own DNA (known as mtDNA), likely because, at the dawn of life, they were independent organisms that eventually entered a symbiotic relationship with eukaryotic cells, such as those found in our bodies.

Unfortunately, as mitochondria produce ATP, they also produce so-called free radicals as a byproduct—atoms with unpaired electrons that seek to “pair up” with other electrons, and to do so, they’ll gladly snatch them from other molecules nearby, damaging them. As free radicals are created by mitochondria, they’re very close to mtDNA, which is thus very susceptible to being damaged and undergoing mutations.

Mitochondria with damaged DNA may become unable to produce ATP or even produce large amounts of waste that cells cannot get rid of. To add insult to injury, mutant mitochondria have a tendency to outlive normal ones and take over the cells in which they reside, turning them into waste production facilities that increase oxidative stress—one of the driving factors of aging.

MitoSENS: How to solve this problem, and how far we’ve got

Cell nuclei are far less exposed to free-radical bombardment than mitochondria, which makes nuclear DNA less susceptible to mutations. For this reason, the cell nucleus would be a much better place for mitochondrial genes, and in fact, evolution has driven around 1000 of them there. Through a technique called allotopic expression, we could migrate the remaining genes to the nucleus and solve the problem of mitochondrial mutations.

Human-made allotopic expression was a mere theory until late 2016, when, thanks to the successful MitoSENS crowdfunding campaign on Lifespan.io, a proof of concept was finally completed. Dr. Matthew O’Connor and his team managed to achieve stable allotopic expression of two mitochondrial genes in cell culture, as reported in the open-access paper[1] they published in the journal Nucleic Acids Research. As Aubrey de Grey himself explains in this video, of the 13 genes SRF is focusing on, it’s now managed to migrate almost four. This had never been done before and is a huge step towards addressing this aspect of aging in humans. In the past few months, the MitoSENS team has presented its results around the world and worked on some problems encountered in the project.

A list of SRF-funded papers on the topic of mitochondrial mutations can be found here. A more detailed description of its intramural MitoSENS research can be found here.

Lysosomal dysfunction

Lysosomes are digestive organelles within cells that dispose of intracellular garbage—harmful byproducts that would otherwise harm cells. Enzymes within lysosomes can dispose of most of the waste that normally accumulates within cells, but some types of waste, collectively known as lipofuscin, turn out to be impossible to break down. As a result, this waste accumulates within the lysosomes, eventually making it harder for them to degrade even other types of waste; in a worst-case scenario, overloaded lysosomes can burst open and spread their toxic contents around.

This eventuality is especially problematic for cells that replicate little or not at all, such as heart and nerve cells—they’ve got all the time in the world to become swamped in waste, which eventually leads to age-related pathologies, such as heart disease and age-related macular degeneration.

LysoSENS: How to solve this problem, and how far we’ve got

As normal lysosomal enzymes cannot break down lipofuscin, a possible therapy could equip lysosomes with better enzymes that can do the job. The approach suggested by SRF originates with ERT—enzyme replacement therapy—for lysosomal storage diseases. This involves identifying enzymes capable of breaking down different types of intracellular junk, identifying genes that encode for these enzymes, and finally delivering the enzymes in different ways, depending on the tissues and cell types involved.

SRF funded a preliminary research project on lipofuscin clearance therapeutics at Rice University[2] and another project relating to atherosclerosis and the clearance of 7-ketocholesterol[3] (a lipofuscin subtype), which eventually spun into Human Rejuvenation Biotechnologies, an early-stage private startup funded by Jason Hope.

A LysoSENS-based approach is currently being pursued by Dr. Kelsey Moody, who used to work at SRF. Dr. Moody has been working on an ERT treatment for age-related macular degeneration. The treatment consists in providing cells of the macula (a region of the eye’s retina) with an enzyme capable of breaking down a type of intracellular waste known as A2E. The treatment, called LYSOCLEAR, is being worked on by Moody’s company Ichor Therapeutics, which earlier this year has announced a series A offering to start Phase I clinical trials of its product.

If LYSOCLEAR proves successful, it could pave the way for future LysoSENS-based therapies to treat lysosomal dysfunction in different tissues.

A list of SRF-funded papers on the topic can be found here.

Cellular senescence

As cells divide, their telomeres—the end-parts of chromosomes protecting them from damage—shorten. Once a critical length has been reached, cells stop dividing altogether and enter a state known as senescence. Senescent cells are known to secrete a cocktail of chemicals called SASP (Senescence Associated Secretory Phenotype), which promotes inflammation and is associated with several age-related conditions.

However, senescent cells are a bit of a double-edged sword; as explained by Professor Judy Campisi during RB2016, as long as they’re not too numerous, senescent cells carry out an anti-cancer function and may promote wound healing; however, too many of them have the opposite effect, and on top of that, they induce neighboring cells to undergo senescence themselves, starting a dangerous spiral.

Normally, senescent cells destroy themselves via programmed cell death, known as apoptosis, and are then disposed of by the immune system, but some of them manage to escape destruction, and as the immune system declines with age, this gets worse.

The result is that late in life, senescent cells have accumulated to unhealthy amounts and significantly contribute to the development of age-related diseases. Osteoarthritis, cardiovascular diseases, cancer, metabolic disorders such as diabetes, and obesity are all linked to the chronic age-related inflammation to which senescent cells contribute.

ApoptoSENS: How to solve this problem, and how far we’ve got

The proposed SENS solution is straightforward: if senescent cells become too numerous, then they need to be purged. Since they are useful in small amounts, the optimal solution would be periodically removing excess senescent cells without eradicating them entirely—and more importantly, leaving other cells unharmed.

This could potentially be achieved by either senolytic drugs or gene therapies that selectively target senescent cells and trigger programmed cell death. Indeed, a great deal of recent focus by researchers have been on finding ways to remove senescent cells using senolytic therapies.

Another approach that could complement senolytics is to address why the immune system stops clearing senescent cells effectively in the first place. This approach focuses on macrophages and other immune cells involved in clearing senescent cells, aiming to reduce inflammation so that these cells begin to function properly again. The irony is that as inflammation rises with age, the immune system that is supposed to clear senescent cells and keep inflammation levels down actually starts to create more inflammation and becomes part of the problem by not doing its job properly.

SRF has funded a number of studies on the subject of cellular senescence, and it’s recently begun working on a project in collaboration with the Buck Institute for Research on Aging, which is focusing on the immune system and its role in clearing senescent cells. Another extramural project, again with the Buck Institute, is focussed on SASP inhibition.

Senescent cell clearance has been all the rage for the past two years or so; Lifespan.io has hosted the MMTP project, which focused on testing senolytics in mice, and this was later followed by CellAge’s project to design synthetic biology-based senolytics.

There are other companies that have joined the race to add senescent cell clearance to the standard toolkit of doctors, such as Unity Biotechnology and Oisin Biotechnologies.

Unity’s approach uses a drug-based approach to senolytics and is scheduled to enter human clinical trials in 2018. A number of other research teams are also developing drug-based approaches to removing senescent cells, and the competition looks set to be fierce in this area in the coming years.

Oisin’s approach, which we discussed here, makes use of suicide genes and hopefully will be tested in clinical trials not too far into the future, thanks to venture funding presently being collected. If this system can be made to work, it will allow very selective targeting of senescent cells by destroying only those giving off a target gene or genes. Thus, if a unique gene expression profile for senescent cells is determined, it would mean only those cells were destroyed, with less risk of off-target effects.

Oisin owes its existence to the SENS Research Foundation and the Methuselah Foundation, which provided the necessary seed funding. Kizoo Technology Ventures has also invested in Oisin.

Extracellular crosslinks

The so-called extracellular matrix is a collection of proteins that act as scaffolding for the cells in our body. This scaffolding is rarely if ever replaced, and a really bad consequence of this is that its parts eventually end up being improperly linked to each other through a process called glycation—the reaction of (mainly) blood sugar with the proteins that make up the extracellular matrix itself.

The resulting cross-links impair the function and movement of the linked proteins, ultimately stiffening the extracellular matrix, which makes organs and blood vessels more rigid. Eventually, this leads to hypertension, high blood pressure, loss of skin elasticity, and organ damage, among other problems.

While there are different types of cross-links—known as AGEs, short for advanced glycation end-products—glucosepane is arguably the worst, being the most common and long-lasting of all, and the body is very ill-equipped to break it down.

GlycoSENS: How to solve this problem, and how far we’ve got

In order to eliminate unwanted cross-links, the SENS approach proposes to develop AGE-breaking molecules that may indeed sever the linkages and return tissues to their original flexibility. Of course, in order to do so, crosslink molecules need to be available for research to attempt to combat them with drugs, and especially in the case of glucosepane, this has been a problem for years.

Glucosepane is a very complex molecule, and very little of it can be extracted from human bodies, and not even in its pure form. This has been greatly hampering the progress of research against glucosepane, but thankfully, this problem is now solved thanks to a collaboration between the Spiegel Lab at Yale University and the SENS Research Foundation, which financially supported the study. It is now possible to fully synthesize glucosepane, allowing for researchers to create it on demand and at a cost-effective price.

The Spiegel Lab’s scientists are now developing anti-glucosepane monoclonal antibodies to cleave unwanted cross-links. The collaboration between the Spiegel Lab and SRF dates all the way back to 2011, but it was in 2015 that the Lab announced its success and published a related paper [4] in the journal Science.

Further information on glucosepane cross-link breakers can be found in this interview with Dr. David Spiegel from Yale University on Fight Aging!; a list of studies on the subject funded or otherwise supported by the SRF is available here.

SRF also worked with the Babraham Institute on a cross-link quantification project.

Let’s help SRF move forward

Readers who wish to donate to SRF to help the organization in its crusade against the ill health of old age can do so by contributing to its winter fundraiser or even becoming SRF patrons. Have a look at SRF’s donation page to find out more.

NB: Dr. Aubrey de Grey (Chief Science Officer and Co-founder of SENS Research Foundation) himself held an AMA (“ask me anything”) on Reddit on December 7, at 14:00 PST (22:00 UTC, 17:00 EST). The questions and Dr. de Grey’s responses can be found here.

Literature

[1] Boominathan, A., Vanhoozer, S., Basisty, N., Powers, K., Crampton, A. L., Wang, X., … & O’Connor, M. S. (2016). Stable nuclear expression of ATP8 and ATP6 genes rescues a mtDNA Complex V null mutant. Nucleic acids research, 44(19), 9342-9357.

[2] Gaspar, J., Mathieu, J., & Alvarez, P. (2016). A rapid platform to generate lipofuscin and screen therapeutic drugs for efficacy in lipofuscin removal. Materials, Methods and Technologies, 10, 1-9.

[3] Mathieu, J. M., Wang, F., Segatori, L., & Alvarez, P. J. (2012). Increased resistance to oxysterol cytotoxicity in fibroblasts transfected with a lysosomally targeted Chromobacterium oxidase. Biotechnology and bioengineering, 109(9), 2409-2415.

[4] Draghici, C., Wang, T., & Spiegel, D. A. (2015). Concise total synthesis of glucosepane. Science, 350(6258), 294-298.

 

About Steve Hill

As a scientific writer and a devoted advocate of healthy longevity technologies, Steve has provided the community with multiple educational articles, interviews, and podcasts, helping the general public to better understand aging and the means to modify its dynamics. His materials can be found at H+ Magazine, Longevity Reporter, Psychology Today, and Singularity Weblog. He is a co-author of the book Aging Prevention for All – a guide for the general public exploring evidence-based means to extend healthy life (in press).

About Nicola Bagalà

Nicola Bagalà has been an enthusiastic supporter and advocate of rejuvenation science since 2011. Although his preferred approach to treating age related diseases is Aubrey de Grey’s suggested SENS platform, he is very interested in any other potential approach as well. In 2015, he launched the blog Rejuvenaction to advocate for rejuvenation and to answer common concerns that generally come with the prospect of vastly extended healthy lifespans. Originally a mathematician graduated from Helsinki University, his scientific interests range from cosmology to AI, from drawing and writing to music, and he always complains he doesn’t have enough time to dedicate to all of them which is one of the reasons he’s into life extension. He’s also a computer programmer and web developer. All the years spent learning about the science of rejuvenation have sparked his interest in biology, in which he’s planning to get a university degree.

About LIFE EXTENSION ADVOCACY FOUNDATION (LEAF)

In 2014, the Life Extension Advocacy Foundation was established as a 501(c)(3) non-profit organization dedicated to promoting increased healthy human lifespan through fiscally sponsoring longevity research projects and raising awareness regarding the societal benefits of life extension. In 2015 they launched Lifespan.io, the first nonprofit crowdfunding platform focused on the biomedical research of aging.

They believe that this will enable the general public to influence the pace of research directly. To date they have successfully supported four research projects aimed at investigating different processes of aging and developing therapies to treat age-related diseases.

The LEAF team organizes educational events, takes part in different public and scientific conferences, and actively engages with the public on social media in order to help disseminate this crucial information. They initiate public dialogue aimed at regulatory improvement in the fields related to rejuvenation biotechnology.

Hallmarks of Aging: Epigenetic Alterations – Article by Steve Hill

Hallmarks of Aging: Epigenetic Alterations – Article by Steve Hill

Steve Hill


Editor’s Note: In this article, Mr. Steve Hill discusses one of the hallmarks of aging – in this case, Epigenetic Alterations. It is part of a paper published in 2013. It divides aging into a number of distinct categories (“hallmarks”) of damage to explain how the aging process works and how it causes age-related diseases [1]. This article was originally published by the Life Extension Advocacy Foundation (LEAF).

                        ~ Kenneth Alum, Director of Publication, U.S. Transhumanist Party, October 18, 2017

What are epigenetic alterations?

The DNA in every one of our cells is identical, with only small variations, so why do our various organs and tissues look so different, and how do cells know what to become?

DNA is modified by the addition of epigenetic information that changes the pattern of gene expression in a cell, suppressing or enhancing the expression of certain genes in a cell as the situation demands. This is how a cell in the liver knows that it needs to develop into a liver cell; the epigenetic instructions make sure that it is given the right orders to become the correct cell type.

At a basic level, these epigenetic instructions make sure that the genes needed to develop into a liver cell are turned on, while the instructions specific to other types of cells are turned off. Imagine if a heart cell was given the wrong instructions and became a bone cell!

How epigenetic alterations accumulate

The aging process can cause alterations to our epigenome, which can lead to alterations in gene expression that can potentially change and ultimately compromise cell function. As an example, epigenetic alterations of the immune system can harm activation and suppress immune cells, thus causing our immune system to fail and leaving us vulnerable to pathogens.

Inflammation is implicated in epigenetic alterations, and studies show that caloric restriction slows the rate of these epigenetic changes [2]. Metabolism and epigenetic alterations are closely linked with inflammation, facilitating a feedback loop leading to ever-worsening epigenetic alterations. Alterations to gene expression patterns are an important driver of the aging process. These alterations involve changes to DNA methylation patterns, histone modification, transcriptional alterations (variance in gene expression) and remodeling of chromatin (a DNA support structure that assists or impedes its transcription).

In the cell, gene expression is activated by hypomethylation (a loss of methylation) or silenced by hypermethylation (an increase of methylation) at a gene location. The aging process causes changes that reduce or increase methylation at different gene locations throughout the body. For example, some tumour suppressor genes become hypermethylated during aging, meaning that they cease functioning, which increases the risk of cancer [3]. Post-translational modifications of histones regulate gene expression by organizing the genome into active euchromatin regions, where DNA is accessible for transcription, or inactive heterochromatin regions, where DNA is compacted and less accessible for transcription. The aging process causes changes to these regions, which changes gene expression.

The aging process also causes an increase in transcriptional noise, which is the primary cause of variance in the gene expression happening between cells [4]. Researchers compared young and old tissues from several species and identified age-related transcriptional changes in the genes encoding key components of inflammatory, mitochondrial, and lysosomal degradation pathways [5].

 Finally, chromatin remodeling alters chromatin from a condensed state to a transcriptionally accessible state, allowing transcription factors and other DNA binding proteins to access DNA and control gene expression.

Conclusion

If we can find ways to reset age-related epigenetic alterations, we can potentially improve cell function, thus improving tissue and organ health.

One potential approach is the use of reprogramming factors, which reset cells to a developmental state, thus reverting epigenetic changes. We have been doing this for over a decade to create induced pluripotent stem cells, and recent work has seen a therapy based on that technique applied to living animals to reset their epigenetic alterations [6]. This reversed a number of age-related changes, and work is now proceeding with the goal of translating this to humans.

Epigenetic alterations might be considered like a program in a computer, but in this case, it is the cell, not a computer, being given instructions. Ultimately, damage causes changes that contribute to the cell moving from an efficient “program” of youth to a dysfunctional one of old age. If we can reset that program, we can potentially address this hallmark of aging, and a number of researchers are working on that right now.

 

Literature

[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[2] Maegawa, S., Lu, Y., Tahara, T., Lee, J. T., Madzo, J., Liang, S., … & Issa, J. P. J. (2017). Caloric restriction delays age-related methylation drift. Nature Communications, 8.
[3] Maegawa, S., Hinkal, G., Kim, H. S., Shen, L., Zhang, L., Zhang, J., … & Issa, J. P. J. (2010). Widespread and tissue specific age-related DNA methylation changes in mice. Genome research, 20(3), 332-340.

[4] Bahar, R., Hartmann, C. H., Rodriguez, K. A., Denny, A. D., Busuttil, R. A., Dollé, M. E., … & Vijg, J. (2006). Increased cell-to-cell variation in gene expression in ageing mouse heart. Nature, 441(7096), 1011-1014.

[5] De Magalhães, J. P., Curado, J., & Church, G. M. (2009). Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics, 25(7), 875-881.

[6] Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., … & Araoka, T. (2016). In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell, 167(7), 1719-1733.

 

About Steve Hill

As a scientific writer and a devoted advocate of healthy longevity technologies, Steve has provided the community with multiple educational articles, interviews, and podcasts, helping the general public to better understand aging and the means to modify its dynamics. His materials can be found at H+ Magazine, Longevity Reporter, Psychology Today, and Singularity Weblog. He is a co-author of the book Aging Prevention for All – a guide for the general public exploring evidence-based means to extend healthy life (in press).

About LIFE EXTENSION ADVOCACY FOUNDATION (LEAF)

In 2014, the Life Extension Advocacy Foundation was established as a 501(c)(3) non-profit organization dedicated to promoting increased healthy human lifespan through fiscally sponsoring longevity research projects and raising awareness regarding the societal benefits of life extension. In 2015 they launched Lifespan.io, the first nonprofit crowdfunding platform focused on the biomedical research of aging.

They believe that this will enable the general public to influence the pace of research directly. To date they have successfully supported four research projects aimed at investigating different processes of aging and developing therapies to treat age-related diseases.

The LEAF team organizes educational events, takes part in different public and scientific conferences, and actively engages with the public on social media in order to help disseminate this crucial information. They initiate public dialogue aimed at regulatory improvement in the fields related to rejuvenation biotechnology.

Hallmarks of Aging: Genomic Instability – Article by Steve Hill

Hallmarks of Aging: Genomic Instability – Article by Steve Hill

Steve Hill


Editor’s Note: In this article, Mr. Steve Hill discusses one of the hallmarks of aging – in this case, Genomic Instability. This article was originally published by the Life Extension Advocacy Foundation (LEAF).

~ Kenneth Alum, Director of Publication, U.S. Transhumanist Party, October 17, 2017

What is genomic instability?

The cells of your body produce a constant flow of proteins and other materials; these are built according to the blueprints contained in our DNA and are vital to cell function and survival. A large amount of information contained in the DNA is ignored during this process, and this is thought to be junk DNA, remnants of our evolutionary past that are no longer used.

However, if a part of the DNA important to cell function mutates or is damaged, the cell can experience a loss of proteostasis, in which the cell produces misfolded proteins. These misfolded proteins can be very harmful, such as when neurons in the brain produce masses of the toxic amyloid beta protein, as seen in Alzheimer’s disease.

Now, the odd dysfunctional cell is not really a huge problem; however, as we get older, an increasing number of cells succumb to this damage and begin to accumulate in tissue over time. Eventually, the number of these damaged cells reaches a point where tissue or organ function is compromised. Normally, the body removes these problem cells via a self-destruct sequence known as apoptosis, a sort of kill switch that senses the damage and destroys the cell in conjunction with the immune system.

Unfortunately, some cells evade apoptosis, taking up space in the tissue and pumping out inflammatory signals that damage the local tissue. These cells are known as senescent cells, and we will be covering them in a later Hallmarks article.

Another possible outcome of damaged DNA is cells that mutate and do not become senescent cells or destroy themselves via apoptosis. These cells continue to replicate, becoming more mutated each time they divide, and if a mutation damages the systems that regulate cell division or switches off the safety mechanisms against tumor formation, this can lead to cancer. The unchecked and rampant cell growth of cancer is probably the most well-known result of genomic instability.

How DNA damage accumulates

There are many ways for DNA to become damaged. UV rays, radiation, chemicals, and tobacco are all examples of environmental stressors that can damage the genome. Even chemotherapy agents designed to kill cancer can also potentially cause DNA damage and senescent cells, leading to later relapse [2].

Finally, even if we avoided all the external threats to our DNA, the body still damages itself. Reactive oxygen and nitrogen species produced during the operation of normal metabolism can damage both DNA and mitochondrial DNA.

Thankfully, we have evolved a robust network of repair systems and mechanisms that can repair most of this damage. We have enzymes that can detect and repair broken strands of DNA or reverse alterations made to base pairs. This repair process is not perfect, and sometimes the DNA is not repaired. This can lead to the cell replication machinery misreading the information contained in the DNA, causing a mutation.

As mutations are passed to daughter cells, the cell tries to prevent this from happening by checking DNA integrity before and after replication. Unfortunately, some cells do manage to slip through the net.

The consequences of DNA damage

A large number of age-related diseases are linked to damaged DNA or faulty DNA repair systems. Alzheimer’s, Parkinson’s, Lou Gehrig’s disease (ALS), and cancer are all the result of genomic instability.

Another example are the progeric diseases. Progerias are congenital disorders that result in rapid aging-like symptoms and a dramatically shortened lifespan, with Hutchinson-Gilford progeria syndrome (HGPS) probably being the most well known. The disease is caused by a defect in Lamin A, a major component of a protein scaffold on the inner edge of the nucleus called the nuclear lamina. The lamina helps organize nuclear processes, such as RNA and DNA synthesis, and lamins are responsible for supporting key proteins in the DNA repair process.

This defect leads to HGPS sufferers only living until their early 20s and developing atherosclerosis, stiff joints, hair loss and wrinkles, and other accelerated aging-like characteristics.

Conclusion

Despite the various repair systems we have evolved, our body is constantly being assaulted from exposure to environmental stressors and even damaged through its own metabolic processes. Coupled with this, our repair systems also decline in effectiveness over time, meaning that DNA damage and mutations are inevitable.

There is some evidence to suggest that caloric restriction may help combat this, but as of now, no drugs or therapies are available yet that can prevent or repair DNA damage. The good news is human trials for DNA repair are launching this year at Harvard, and Dr. David Sinclair and other researchers are also working on their own solutions.

For the time being, the best we can do is to avoid risks, such as excessive sun exposure, industrial chemicals, smoking, and, of course, staying away from radioactive waste; there are no comic-book superpowers from these mutations!

Literature

[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[2] Demaria, M., O’Leary, M. N., Chang, J., Shao, L., Liu, S., Alimirah, F., … & Alston, S. (2017). Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer discovery, 7(2), 165-176.

About Steve Hill

As a scientific writer and a devoted advocate of healthy longevity technologies, Steve has provided the community with multiple educational articles, interviews, and podcasts, helping the general public to better understand aging and the means to modify its dynamics. His materials can be found at H+ Magazine, Longevity Reporter, Psychology Today, and Singularity Weblog. He is a co-author of the book Aging Prevention for All – a guide for the general public exploring evidence-based means to extend healthy life (in press).

About LIFE EXTENSION ADVOCACY FOUNDATION (LEAF)

In 2014, the Life Extension Advocacy Foundation was established as a 501(c)(3) non-profit organization dedicated to promoting increased healthy human lifespan through fiscally sponsoring longevity research projects and raising awareness regarding the societal benefits of life extension. In 2015 they launched Lifespan.io, the first nonprofit crowdfunding platform focused on the biomedical research of aging.

They believe that this will enable the general public to influence the pace of research directly. To date they have successfully supported four research projects aimed at investigating different processes of aging and developing therapies to treat age-related diseases.

The LEAF team organizes educational events, takes part in different public and scientific conferences, and actively engages with the public on social media in order to help disseminate this crucial information. They initiate public dialogue aimed at regulatory improvement in the fields related to rejuvenation biotechnology.