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Piano Sonata No.3 in G minor, “Death is Wrong” – Composed by Adriano G. Santos, Inspired by the “Death is Wrong” Book Written by Gennady Stolyarov II

Piano Sonata No.3 in G minor, “Death is Wrong” – Composed by Adriano G. Santos, Inspired by the “Death is Wrong” Book Written by Gennady Stolyarov II

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Adriano G. Santos


Listen to the complete Piano Sonata No. 3 in G minor, “Death is Wrong”, by Adriano G. Santos on YouTube here. The YouTube video also contains the complete score for the sonata.

Program Notes
Piano Sonata No. 3 in G minor
“Death is Wrong”
Composer: Adriano G. Santos

Inspired by the book Death is Wrong, written by Gennady Stolyarov II

This piano composition was completed on December 26, 2025, and was conceived as a programmatic work inspired by the book Death is Wrong, written by Gennady Stolyarov II.

When I started reading the book I felt so identified with some of the contents due to special circumstances I was facing at that time, like the extreme frustration I have always had towards the senescence of piano playing from a physical perspective, and my mother’s tragic femur rupture.

As I was reading the book, very strong musical desires of composing came to my mind and heart, and I almost immediately felt the need to create a new work of programmatic nature based on the contents of this book.

The composition structure is based on the sonata form. The music starts on page 4 from the book, when Gennady asks his mother, “But why do people die? Do they do anything bad to deserve it?” (1), and his mother answers with a perfectly understandable constant justification of human mortality.

The introduction of the sonata tries to mirror this with a dialogue in A major (V/V) between 2 motivic cells in which the first one is made of an eighth-note, 6 quarter-notes organized in triplets asking questions regarding the existence of death, and a question mark represented as a half-note (Fig. A).

The second motif consisting of eight notes alternated with 16th notes answer this question justifying human mortality (Fig. B).

This same dialogue is transposed to the dominant and tonic keys (V/I).


Motifs illustrated in Figures A and B came to my mind almost arbitrarily while composing the introduction, but after a short analysis of different masterpieces, Alkan’s Scherzo Diabolico knocked at my door, and I realized that, very conveniently, the first four notes are a fragmented diminution of my original motif that started the musical dialogue questioning human mortality.

I made a variation of the beginning motifs of the Alkan Etude (Fig. 1), and I used this to express the following statement from Stolyarov’s book: “It is wrong!” I exclaimed. “People should not die!” (2) (Fig. 1.1).


The purposefully forward motion filled with an anxious and passionate emergency of the Alkan Etude, Opus 39, Number 3 in G minor, was ideal for the main theme of my sonata, which I titled, “Deeply and passionately attached to eternal life”.

Unfortunately, as of today, life extension within the context of human eternal life could be perceived as “unfulfilled love”, and a perfect example of this is Beethoven, whose music is often marked by ambiguity and unrequited love, due partially to his relationships, disappointment, suffering, and deafness. Interestingly, I felt a strong call to go through the first movement of his E minor Sonata, Op. 90, and when I reached the secondary theme in B minor, I could sense a painful yearning for fulfillment in those recurrent minor seconds (G/F#), and I immediately knew that my main theme needed that same persistent interval.

In the illustration above in Fig. C, Alkan’s rhythmic and technical patterns give a sense of urgency and anxiety to the desire of fulfillment.

The secondary theme in E-flat major addresses specific lines from Stolyarov’s book. The motivic cells are a fragmentation of the main theme, and the overall idea of the initial fragmented motif of the first 8 measures (mm. 109-116) is based on two crucial questions from the book on page 18: “What could you do if you could live for hundreds, thousands, tens of thousands of years? What could you do if you could live even longer than that?”

When the motif suffers another fragmentation in measures 117-128, the music is answering the 2 questions aforementioned by emphasizing the benefits of life extension addressed in the book: “You could read many of the greatest books ever written, you could become a great composer, you could live to see the most amazing scientific and technological wonders…”


In measures 129-133, the original fragmented motif comes back as a desire to fulfill those possibilities through life extension.

As the music becomes denser through transposition, secondary dominants, diminished harmonies, and modulations, the composition is trying to express advice and danger warnings: “The younger you apply this, the more chances you will have to defeat death” and “Be careful of the different dangers that empower senescence and death.”




The Development begins with a motif derived from the original question at the beginning of the introduction, only this time the cell is broader and there is no longer a question of “Why do we have to die?” but a deep thinking of the possibility that “Death is Wrong.”

As the Development progresses, this possibility becomes stronger and more definitive (mm. 176-224).

From measures 200-215, music advances chromatically, and by every half-step a new discovery, experiment, or theory about the most promising scientific efforts of our time enriches life-extension possibilities.

Constant chromatic evolution gives a sensation of confidence and power that results ideal in trying to reflect musically the achievements of experiments with small animals like mice, the fact of the existence of huge lifespans in lobsters, the potential of medical therapies to reverse biological aging in humans from Dr. Aubrey de Grey (3), and other scientific breakthroughs (Fig. H1).


The motif can be expressed into lyrics to make the idea more approachable as in Fig. H2, where you can see only the top notes of the same motifs.

After this chain of chromatic events, an octave virtuosic section derived from the 2nd warning in Fig. H, takes place and represents the struggle against death, senescence, diseases, accidents, natural disasters, and sheep-like mentality (mm. 225-309).

This intense and ferocious section not only develops the second warning of the exposition ending but also goes into a deeper and more powerful chromatic evolution.

The closing section is greatly influenced by Liszt’s B minor Ballade, where the development seems to come to an end, and a sequence of broken octaves brings back the fire leading to a climatic point. In my sonata, when the repeated D quarter-notes die away, suddenly, an identical sequence of E-flat quarter notes brings back the final part of the development, as if the phoenix were rising from the ashes. This continuation in E-flat is a small musical symbol that represents “Musical Life Extension” (Fig. H3).


As the development ending gradually reaches greater intensity, the main motivic cells of the exposition are battling for supremacy as tension is built throughout fifty-eight measures (mm. 354-412), full of energy and yearning.

The recapitulation takes place as the highest climatic point where the main theme is disguised as “development”. Technical virtuosic patterns from Liszt’s Paganini and Transcendental Etudes are ideal for expressing one of the most powerful possibilities I’ve ever read in a book: “Maybe the person who will conquer death… is you.”

During my learning process of some of the hardest piano works by Liszt, I really felt that I was climbing a mountain, and that’s what I tried to mirror in this climatic passage (Fig. H4 & H5). Thus, I believe that humanity has the privilege of living in a present era that is at a considerable height on the mountain of the conquest of death.


The secondary theme opens with a follow-up question to the original in the exposition, which was, “What could you do if you could live for thousands of years or even longer?”

In the recapitulation we no longer have a personal question that answers with dreams and desires, but a follow-up one about the world and humanity in general: “What would happen if this is achieved in human beings?”

New dreams would arise in the human need and creativity for new ramifications of life extension that could result in an even more fulfilling eternal life.

This evolution can go from quantifying and manipulating dopamine levels in humans, biomarkers at their final peak through superb innovations of data analytics, multi-omics, and digital health, to even more astonishing possibilities that are considered today science fiction, like past-time travel through the manipulation of gravity and rotation of wormholes. Imagine saving a loved one from dying in the past, or even sharing life-extension benefits with great minds like Einstein, Beethoven, Shakespeare, and many others.

In the bridge that connects to the Coda (mm. 499-532), the music becomes more chromatic and rotatory, trying to create a transcendental effect that pushes the momentum forward towards the Coda.

The Coda section arrives trying to express that the need for eternal life is no longer only a strong desire but a passionate fulfilling encounter that is enriched by life-extension ramifications mentioned in Theme B.

After such a heartfelt outburst of measures 533-579, the motto perpetuo of D quarter-notes from the development comes back in an even more mysterious output on measures 580-627 and followed by another symbolic “extension”.

The main theme takes a gradually strong and determining lead that finishes the work with a very convenient influence of Liszt’s Funérailles ending that releases a triumphant and solemn return of the secondary theme (mm. 628-688).

References

1, 2, 3. Stolyarov II, G. 2013. Death is Wrong. Rational Argumentator Press. https://rationalargumentator.com/Death_is_Wrong_Second_Edition_Full.pdf

Fig. 1. Alkan, C.-V. (1979). Douze études dans tous les tons mineurs, Op. 39, No. 3. (R. Lewenthal, Ed.). Schirmer.

Fig. H4. Liszt, F., 1851. Grandes études de Paganini. S. 141, No. 6, Variation 11. Shonenberg, R. Cocks & Co. (London).

Listen to the complete Piano Sonata No. 3 in G minor, “Death is Wrong”, by Adriano G. Santos on YouTube here.

Listen to the compositions of Adriano G. Santos on his YouTube channel.

Fifth Enlightenment Salon – Discussions on Longevity, Gene Therapy, Overcoming Disabilities, Animal Lifespans, Education, and Privacy

Fifth Enlightenment Salon – Discussions on Longevity, Gene Therapy, Overcoming Disabilities, Animal Lifespans, Education, and Privacy

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Gennady Stolyarov II
Bill Andrews
James Kohagen
Bobby Ridge
John Murrieta

On October 13, 2018, in the spirit of the Age of Enlightenment and its furtherance today, Gennady Stolyarov II, Bill Andrews, James Kohagen, Bobby Ridge, and John Murrieta met for the fifth interdisciplinary discussion – hosted by Mr. Stolyarov – on science, culture, education, advocacy, and policy. Subjects discussed included the following:

– The recent RAAD Fest 2018 in San Diego
– Developments in the field of gene therapy
– Advances in epidural stimulation for treating and overcoming spinal-cord injuries
– Long-lived organisms and their similarities and dissimilarities to humans
– How animal experiments can become more humane
– How contemporary science still has far to go to accumulate even fairly basic information about certain organisms
– How the study of lifespans can be included in educational curricula starting at early childhood
– Whether privacy will remain in a more technologically interconnected future.

Join the U.S. Transhumanist Party for free, no matter where you reside by filling out an application form that takes less than a minute.

Find out about Death is Wrong – the illustrated children’s book on indefinite life extension.

“Squeak” – Art by Laura Katrin Weston, a.k.a. Katrin Brunier

“Squeak” – Art by Laura Katrin Weston, a.k.a. Katrin Brunier

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Laura Katrin Weston


Commentary by Gennady Stolyarov II: “Squeak” is a print by Dr. Laura Katrin Weston, a.k.a. Katrin Brunier, the original exemplar of which I received in November 2017 due to my donation to the successful MouseAge crowdfunding campaign by Lifespan.io.

It is fitting for a project on mouse longevity to involve at least one image of mice – creatures whom life has unfortunately dealt a bad hand, due to their short lifespans (only 3 years for even long-lived mice in the absence of medical intervention), difficulty in getting along with humans, and unnecessary attrition due to disposal practices after lab experiments. “Squeak” invites the viewer to appreciate mice a bit more; if we can extend their lives significantly, we stand a decent chance of achieving dramatic extension of our own lifespans.  Perhaps we can also give some of the mice a break by using photographic markers of aging in experiments, as the MouseAge project seeks to do.

Here, the mice are depicted scurrying along a narrow circular path. The golden circle, with rays emanating outward represents perhaps the great hope that these creatures unknowingly provide to us. One may wonder, as I have done over many months of reflecting on this work, whether these are mutant, two-tailed mice, or whether they each just have their ordinary curly tails, and the track along which they move might simply be painted in the same colors and textures as their tails. (Well, in actuality it is indeed painted that way!) Mutant or not, these mice are rather extraordinary in having become emblems of a species that has added much to our understanding. Unlike most of their brethren to date, these mice have earned their extreme longevity through Laura Katrin Weston’s brush.

You can find more work by Dr. Laura Katrin Weston at the Katrin Brunier Gallery, an Ethical Investment-Grade Art Gallery for the Neo-Renaissance Era (see its Instagram page). Proceeds from art sales at the Katrin Brunier Gallery will go to support causes such as medical research and conservation.

MILE / U.S. Transhumanist Party Interview with Ira Pastor of Bioquark, Inc.

MILE / U.S. Transhumanist Party Interview with Ira Pastor of Bioquark, Inc.

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The New Renaissance Hat

G. Stolyarov II

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Gennady Stolyarov II, Chairman of the U.S. Transhumanist Party, was honored to interview entrepreneur and pharmaceutical industry veteran Ira Pastor for MILE – the Movement for Indefinite Life Extension – the U.S. Transhumanist Party, and the Nevada Transhumanist Party. The hour-long conversation delved into a variety of interrelated subject areas, including regeneration and repair mechanisms in animals, potential applications in humans, development of substances and treatments that could achieve victories against diseases and lead to longer lifespans, political and regulatory implications for the development of such substances, the importance of awareness of this research within the broader society, and even a “moonshot” project called ReAnima for repairing traumatic injury to organs and tissues that would otherwise cause irreversible death in accident victims.

This interview took place on Saturday, February 11, 2017, at 10 a.m. U.S. Pacific Time.

Read about Bioquark here.

Read about Mr. Pastor here.

Join the U.S. Transhumanist Party for free here.

Visit and like the MILE – Movement for Indefinite Life Extension – Facebook page here.

It’s Time to Postpone Your Appointment with the Grim Reaper – Article by Gerrard Jayaratnam

It’s Time to Postpone Your Appointment with the Grim Reaper – Article by Gerrard Jayaratnam

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The New Renaissance HatGerrard Jayaratnam
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How long would you like to live for? Is there a limit to how long we can live for? These are not questions you hear often, but do not be surprised if they are repeated more frequently in the future. The reason? Life extension. It is the concept of living well beyond the average lifespan. [1]

Humans are already living longer due to vaccines and improvements in sanitation. [2] The World Health Organization reported that the average life expectancy at birth increased from 48 years in 1955 to 65 years in 1995, and is projected to rise to 73 years by 2025. [3] As medical techniques continue to improve, we are more inclined than ever to pursue life extension. [1] Indeed, from the Epic of Gilgamesh to China’s First Emperor, prolonging life has been an ever-present thought in society. [4, 5] Both individuals failed to escape death, but the idea of life extension ironically lives on. Even so, is it truly possible and what should upcoming doctors and scientists consider if they are to join the most ambitious of quests?

The “Horcruxes” of reality 

In the fictional Harry Potter series, “Horcruxes” were objects where people could hide a fragment of their soul in an attempt to take one step towards immortality. [6] Of course, humans cannot split their souls and hide them in objects, but there are several proposed means by which life extension may be achieved. [1] This is a testimony to the progress within the life extension field, but there remains much room for improvement.

Eat less, live more

Caloric restriction (CR) is one proposed method for life extension. [1] In the CALERIE (Comprehensive Assessment of Long term Effects of Reducing Intake of Energy) trial, 218 non-obese humans were randomised to either a control group or an intervention group. The latter aimed for a 25% reduction from baseline energy intake. At the end of the 2-year study period, the intervention group had significantly greater reductions in circulating levels of TNF-α – an inflammatory marker involved in many age-related diseases. [7] Dr Alexander Miras, winner of the 2014 Nutrition Society Cuthbertson Medal for his research on bariatric surgery, acknowledges that the study was a “good first step,” but argues that “the evidence in humans is lacking.” “A definitive RCT (randomised controlled trial),” Dr Miras continues, “would be very hard, if not impossible.” He also spots a glaring consequence of CR. “My personal approach is to avoid caloric restriction as this leads to hunger which is an unpleasant feeling. I would rather live a shorter life, but enjoy my food.”

Manipulating telomerase

One alternative is modulating telomerase activity – as attempted with the anti-ageing TA-65MD® supplement. [8] Telomeres protect the ends of chromosomes [9]; they resemble the aglets on the ends of shoelaces. Just as shoelaces would unravel without the aglet, chromosomes would lose vital DNA sequences in the absence of telomeres. [9] Our cells divide over time, causing telomeres to shorten. Once the telomere becomes too short, cell division ceases, and short telomeres correlate with cellular ageing. [10] Telomerase is an enzyme that can oppose telomere shortening [10] – it was what Hamlet was to King Claudius; what exercise is to obesity; and what junior doctors, in England, will be to Jeremy Hunt.

Reactivating telomerase in telomerase-deficient mice reversed both neurodegeneration and degeneration of other organs. [11] This proved the concept that boosting telomerase activity could have anti-ageing effects, but there is little proof that this occurs in humans. While the mice were telomerase-deficient, humans normally have some telomerase activity. It is like giving food to someone who has been fasting for hours and to someone who has just eaten a three-course meal – the starved individual would unquestionably benefit more. A 12-month long RCT, involving 117 relatively healthy individuals (age range: 53-87), found that low-dose TA-65 significantly increased telomere length when compared to placebo. High-dose TA-65, however, failed to do so. [12]

Dancing with the devil

What is more worrying than treatments that may be ineffective? Side effects. Telomerase is a double-edged sword and by reducing telomere attrition, it can promote unlimited cell division and cancer. [9] Elizabeth Blackburn, co-winner of the 2009 Nobel Prize in Physiology or Medicine for her role in the discovery of telomerase, has doubts about exploiting the enzyme. Speaking to TIME magazine, she said, “Cancers love telomerase, and a number of cancers up-regulate it like crazy. . . . My feeling would be that if I take anything that would push my telomerase up, I’m playing with fire.” [13]

A cauldron of rewards

CR and boosting telomerase activity are just a small sample of life extending techniques, yet there is the notion that such techniques will be intertwined with risks. However, risks are always weighed against rewards, and Gennady Stolyarov, editor-in-chief of The Rational Argumentator and Chief Executive of the Nevada Transhumanist Party, believes life extension would bring “immense and multifaceted” rewards. “The greatest benefit is the continued existence of the individual who remains alive. Each individual has incalculable moral value and is a universe of ideas, experiences, emotions, and memories. When a person dies, that entire universe is extinguished . . . This is the greatest possible loss, and should be averted if at all possible.” Stolyarov also envisages “major savings to healthcare systems” and that “the achievement of significant life extension would inspire many intelligent people to try to solve other age-old problems.”

Former chairman of the President’s Council on Bioethics, Leon Kass, disagrees with this view and argues that mortality is necessary for “treasuring and appreciating all that life brings.” [14] Hence, increased longevity could lead to an overall reduction in productivity over one’s lifetime. Perhaps Kass is correct, but the array of potential benefits makes it seem unwise to prematurely dismiss life extension. In fact, a survey, which examined the opinions of 605 Australians on life extension, highlighted further benefits – 23% of participants said they could “spend more time with family” and 4% cited the opportunity to experience future societies. [15]

Learning from our mistakes

Conversely, life extension may result in people enduring poor health for longer periods. 28% of participants in the Australian survey highlighted this concern. [15] Current trends in life expectancy reinforce their fears. Professor Janet Lord, director of the Institute of Inflammation and Ageing at the University of Birmingham, explains, “Currently, in most countries in the developed world, life expectancy is increasing at approximately 2 years per decade, but healthspan (the years spent in good health) is only increasing at 1.7 years. This has major consequences . . . as more of later life is spent in poor health.” This is a consequence of treating “killer diseases” – according to Dr Felipe Sierra, director of the Division of Aging Biology at the National Institute on Aging. “The current model in biomedicine,” says Dr Sierra, “is to treat one disease at a time. Let’s imagine you have arthritis; cancer; and are starting to develop Alzheimer’s disease. So what do we do? We treat you for cancer. You now live longer with Alzheimer’s disease and arthritis.” A better approach is clear to Dr Sierra who stresses the importance of compression of morbidity – “the goal is to live longer with less time spent being sick.”

Learning from our successes

Even with Dr Sierra’s approach, individual boredom and social implications, including overpopulation, would still be problems.[16] According to Stolyarov, the boredom argument does not hold up when facing “human creativity and discovery.” He believes humans could never truly be bored as “the number of possible pursuits increases far faster than the ability of any individual to pursue.”

In his novel Death is Wrong, Stolyarov explained that the idea that society could not cope with a rapidly expanding population was historically inaccurate. The current population “is the highest it has ever been, and most people live far longer, healthier, prosperous lives than their ancestors did when the Earth’s population was hundreds of times smaller.” [16] If it has been achieved in the past, who is to say our own society – one far more advanced than any before it – cannot adapt?

The verdict

Life extension research is quietly progressing, and there is a good chance that it will eventually come to fruition. Although there are doubts about current techniques, Dr Sierra draws attention to novel interventions, such as rapamycin, which “delay ageing in mice.” He concludes that the next challenge is to “develop measures than can predict whether an intervention works in a short-term assay.” Such measures would provide the scaffolding for future clinical trials that test life extension techniques.

Given what may be gained, it is no surprise that artificially prolonging life is exciting some in the same way the Tree of Knowledge tempted Eve. The impact on society? Impossible to predict. It would undoubtedly be a big risk, but perhaps in this complex and uncertain scenario, we ought to remember the words of the poet Thomas Stearns Eliot: “Only those who will risk going too far can possibly find out how far one can go.” [17]

Gerrard Jayaratnam is a student of Biomedical Science at Imperial College London.

References

  1. Stambler I. A History of Life-Extensionism in the Twentieth Century. Ramat Gan: CreateSpace Independent Publishing Platform; 2014.
  2. National Institute on Aging. Living Longer. 2011. https://www.nia.nih.gov/research/publication/global-health-and-aging/living-longer.
  3. World Health Organization. 50 Facts: Global Health situation and trends 1955-2025. 2013. http://www.who.int/whr/1998/media_centre/50facts/en/.
  4. Encyclopaedia Britannica. Epic of Gilgamesh. 2016. http://www.britannica.com/topic/Epic-of-Gilgamesh.
  5. Lloyd DF. The Man Who Would Cheat Death and Rule the Universe. Vision. 2008. http://www.vision.org/visionmedia/history-shi-huang-emperor-china/5818.aspx.
  6. Rowling JK. Harry Potter and the Half-Blood Prince. London: Bloomsbury Publishing; 2005.
  7. Ravussin E, Redman LM, Rochon J, et al. A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity. J Gerontol A Biol Sci Med Sci 2015;70:1097-1104.
  8. A. Sciences. What is TA-65®? (n.d.) [Accessed 3rd April 2016]. https://www.tasciences.com/what-is-ta-65/.
  9. De Jesus BB, Blasco MA. Telomerase at the intersection of cancer and aging. Trends Genet 2013;29:513-520.
  10. A. Sciences. Telomeres and Cellular Aging. (n.d.) [Accessed 3rd April 2016]. https://www.tasciences.com/telomeres-and-cellular-aging/.
  11. Jaskelioff M, Muller FL, Paik JH, et al. Telomerase reactivation reverses tissue degeneration in aged telomerase deficient mice. Nature 2011;469:102-106.
  12. Salvador L, Singaravelu G, Harley CB, et al. A Natural Product Telomerase Activator Lengthens Telomeres in Humans: A Randomized, Double Blind, and Placebo Controlled Study. Rejuvenation Res 2016; ahead of print. doi:10.1089/rej.2015.1793.
  13. Kluger J. The antiaging power of a positive attitude. TIME. 2015.
  14. Than K. The Psychological Strain of Living Forever. Live Science. 2006. http://www.livescience.com/10469-psychological-strain-living.html.
  15. Partridge B, Lucke J, Bartlett H, et al. Ethical, social, and personal implications of extended human lifespan identified by members of the public. Rejuvenation Res 2009;12:351-357.
  16. Stolyarov II G. Death is Wrong. 2nd ed. Carson City, Nevada: Rational Argumentator Press; 2013.
  17. The Huffington Post. 11 Beautiful T.S. Eliot Quotes. 2013. http://www.huffingtonpost.com/2013/09/26/ts-eliot-quotes_n_3996010.html.
Major Mouse Testing Program Crowdfunding Campaign Announcement by International Longevity Alliance

Major Mouse Testing Program Crowdfunding Campaign Announcement by International Longevity Alliance

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The New Renaissance HatInternational Longevity Alliance

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Editor’s Note: The Rational Argumentator strongly supports the Major Mouse Testing Project crowdfunding campaign, and I have personally pledged $100 to this effort. Furthermore, I am honored that copies of my illustrated children’s book Death is Wrong are being made available as rewards for certain tiers of contributors to this research fundraiser.

~ Gennady Stolyarov II, Editor-in-Chief, The Rational Argumentator, May 11, 2016

The International Longevity Alliance is conducting a crowdfunding campaign to support the investigation of senolytic drugs’ potential to extend life. The team is going to study the combination of three senolytic drugs – Dasatinib, Venetoclax, and Quercetin – in mice, to see if the removal of senescent cells can ensure extended maximum lifespan. With highly devoted scientists and volunteers working for MMTP, the project needs only $60,000 to begin this experiment, as the researchers would need only to buy the mice and pay for their housing, the substances to test, and the battery of tests to analyze health changes.

Will you help to fund this research? Then please go to Lifespan.io, and choose the donation that suits you best and receive the deepest gratitude of the team and a nice useful souvenir to remember your input into the investigation of longevity therapies!

MMTP_Project1_StairFind out more about the International Longevity Alliance here.

The Two Faces of Aging: Cancer and Cellular Senescence – Article by Adam Alonzi

The Two Faces of Aging: Cancer and Cellular Senescence – Article by Adam Alonzi

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The New Renaissance Hat
Adam Alonzi
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This article is republished with the author’s permission. It was originally posted on Radical Science News.

hELA-400x300Multiphoton fluorescence image of HeLa cells.

Aging, inflammation, cancer, and cellular senescence are all intimately interconnected. Deciphering the nature of each thread is a tremendous task, but must be done if preventative and geriatric medicine ever hope to advance. A one-dimensional analysis simply will not suffice. Without a strong understanding of the genetic, epigenetic, intercellular, and intracellular factors at work, only an incomplete picture can be formed. However, even with an incomplete picture, useful therapeutics can be and are being developed. One face is cancer, in reality a number of diseases characterized by uncontrolled cell division. The other is degradation, which causes a slue of degenerative disorders stemming from deterioration in regenerative capacity.

Now there is a new focus on making geroprotectors, which are a diverse and growing family of compounds that assist in preventing and reversing the unwanted side effects of aging. Senolytics, a subset of this broad group, accomplish this feat by encouraging the removal of decrepit cells. A few examples include dasatinib, quercetin, and ABT263. Although more research must be done, there are a precious handful of studies accessible to anyone with the inclination to scroll to the works cited section of this article. Those within the life-extension community and a few enlightened souls outside of it already know this, but it bears repeating: in the developed world all major diseases are the direct result of the aging process. Accepting this rather simple premise, and you really ought to, should stoke your enthusiasm for the first generation of anti-aging elixirs and treatments. Before diving into the details of these promising new pharmaceuticals, nanotechnology, and gene therapies we must ask what is cellular senescence? What causes it? What purpose does it serve?

Depending on the context in which it is operating, a single gene can have positive or negative effects on an organism’s phenotype. Often the gene is exerting both desirable and undesirable influences at the same time. This is called antagonistic pleiotropy. For example, high levels of testosterone can confer several reproductive advantages in youth, but in elderly men can increase their likelihood of developing prostate cancer. Cellular senescence is a protective measure; it is a response to damage that could potentially turn a healthy cell into a malignant one. Understandably, this becomes considerably more complex when one is examining multiple genes and multiple pathways. Identifying all of the players involved is difficult enough. Conboy’s famous parabiosis experiment, where a young mouse’s system revived an old ones, shows that alterations in the microenviornment, in this case identified and unidentified factors in the blood of young mice, can be very beneficial to their elders. Conversely, there is a solid body of evidence that shows senescent cells can have a bad influence on their neighbors. How can something similar be achieved in humans without having to surgically attach a senior citizen to a college freshman?

By halting its own division, a senescent cell removes itself as an immediate tumorigenic threat. Yet the accumulation of nondividing cells is implicated in a host of pathologies, including, somewhat paradoxically, cancer, which, as any life actuary’s mortality table will show, is yet another bedfellow of the second half of life. The single greatest risk factor for developing cancer is age. The Hayflick Limit is well known to most people who have ever excitedly watched the drama of a freshly inoculated petri dish. After exhausting their telomeres, cells stop dividing. Hayflick et al. astutely noted that “the [cessation of cell growth] in culture may be related to senescence in vivo.” Although cellular senescnece is considered irreversible, a select few cells can resume normal growth after the inactivation of the p53 tumor suppressor. The removal of p16, a related gene, resulted in the elimination of the progeroid phenotype in mice. There are several important p’s at play here, but two are enough for now.

Our bodies are bombarded by insults to their resilient but woefully vincible microscopic machinery. Oxidative stress, DNA damage, telomeric dysfunction, carcinogens, assorted mutations from assorted causes, necessary or unnecessary immunological responses to internal or external factors, all take their toll. In response cells may repair themselves, they may activate an apoptotic pathway to kill themselves, or just stop proliferating. After suffering these slings and arrows, p53 is activated. Not surprisingly, mice carrying a hyperactive form of p53 display high levels of cellular senescence. To quote Campisi, abnormalities in p53 and p15 are found in “most, if not all, cancers.” Knocking p53 out altogether produced mice unusually free of tumors, but those mice find themselves prematurely past their prime. There is a clear trade-off here.

In a later experiment Garcia-Cao modified p53 to only express itself when activated. The mice exhibited normal longevity as well as an“unusual resistance to cancer.” Though it may seem so, these two cellular states are most certainly not opposing fates. As it is with oxidative stress and nutrient sensing, two other components of senescence or lack thereof, the goal is not to increase or decrease one side disproportionately, but to find the correct balance between many competing entities to maintain healthy homeostasis. As mentioned earlier, telomeres play an important role in geroconversion, the transformation of quiescent cells into senescent ones. Meta-analyses have shown a strong relationship between short telomeres and mortality risk, especially in younger people. Although cancer cells activate telomerase to overcome the Hayflick Limit, it is not entirely certain if the activation of telomerase is oncogenic.

majormouse

SASP (senescence-associated secretory phenotype) is associated with chronic inflammation, which itself is implicated in a growing list of common infirmities. Many SASP factors are known to stimulate phenotypes similar to those displayed by aggressive cancer cells. The simultaneous injection of senescent fibroblasts with premalignant epithelial cells into mice results in malignancy. On the other hand, senescent human melanocytes secrete a protein that induces replicative arrest in a fair percentage of melanoma cells. In all experiments tissue types must be taken into account, of course. Some of the hallmarks of inflammation are elevated levels of IL-6, IL-8, and TNF-α. Inflammatory oxidative damage is carcinogenic and an inflammatory microenvironment is a good breeding ground for malignancies.

Caloric restriction extends lifespan in part by inhibiting TOR/mTOR (target of rapamycin/mechanistic target of rapamycin, also called  the mammalian target of rapamycin). TOR is a sort of metabolic manager, it receives inputs regarding the availability of nutrients and stress levels and then acts accordingly. Metformin is also a TOR inhibitor, which is why it is being investigated as a cancer shield and a longevity aid. Rapamycin has extended average lifespans in all species tested thus far and reduces geroconversion. It also restores the self-renewal and differentiation capacities of haemopoietic stem cells. For these reasons the Major Mouse Testing Program is using rapamycin as its positive control. mTOR and p53 dance (or battle) with each other beautifully in what Hasty calls the “Clash of the Gods.” While p53 inhibits mTOR1 activity, mTOR1 increases p53 activity. Since neither metformin nor rapamycin are without their share of unwanted side effects, more senolytics must be explored in greater detail.

Starting with a simple premise, namely that senescent cells rely on anti-apoptotic and pro-survival defenses more than their actively replicating counterparts, Campisi and her colleagues created a series of experiments to find the “Achilles’ Heel” of senescent cells. After comparing the two different cell states, they designed senolytic siRNAs. 39 transcripts were selected for knockdown by siRNA transfection, and 17 affected the viability of their target more than healthy cells. Dasatinib, a cancer drug, and quercitin, a common flavonoid found in common foods, have senolytic properties. The former has a proven proclivity for fat-cell progenitors, and the latter is more effective against endothelial cells. Delivered together, they they remove senescent mouse embryonic fibroblasts. Administration into elderly mice resulted in favorable changes in SA-BetaGAL (a molecule closely associated with SASP) and reduced p16 RNA. Single doses of D+Q together resulted in significant improvements in progeroid mice.

If you are not titillated yet, please embark on your own journey through the gallery of encroaching options for those who would prefer not to become chronically ill, suffer immensely, and, of course, die miserably in a hospital bed soaked with several types of their own excretions―presumably, hopefully, those who claim to be unafraid of death have never seen this image or naively assume they will never be the star of such a dismal and lamentably “normal” final act. There is nothing vain about wanting to avoid all the complications that come with time. This research is quickly becoming an economic and humanitarian necessity. The trailblazers who move this research forward will not only find wealth at the end of their path, but the undying gratitude of all life on earth.

Adam Alonzi is a writer, biotechnologist, documentary maker, futurist, inventor, programmer, and author of the novels “A Plank in Reason” and “Praying for Death: Mocking the Apocalypse”. He is an analyst for the Millennium Project, the Head Media Director for BioViva Sciences, and Editor-in-Chief of Radical Science News. Listen to his podcasts here. Read his blog here.

References

Blagosklonny, M. V. (2013). Rapamycin extends life-and health span because it slows aging. Aging (Albany NY), 5(8), 592.

Campisi, Judith, and Fabrizio d’Adda di Fagagna. “Cellular senescence: when bad things happen to good cells.” Nature reviews Molecular cell biology 8.9 (2007): 729-740.

Campisi, Judith. “Aging, cellular senescence, and cancer.” Annual review of physiology 75 (2013): 685.

Hasty, Paul, et al. “mTORC1 and p53: clash of the gods?.” Cell Cycle 12.1 (2013): 20-25.

Kirkland, James L. “Translating advances from the basic biology of aging into clinical application.” Experimental gerontology 48.1 (2013): 1-5.

Lamming, Dudley W., et al. “Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity.” Science 335.6076 (2012): 1638-1643.

LaPak, Kyle M., and Christin E. Burd. “The molecular balancing act of p16INK4a in cancer and aging.” Molecular Cancer Research 12.2 (2014): 167-183.

Malavolta, Marco, et al. “Pleiotropic effects of tocotrienols and quercetin on cellular senescence: introducing the perspective of senolytic effects of phytochemicals.” Current drug targets (2015).

Rodier, Francis, Judith Campisi, and Dipa Bhaumik. “Two faces of p53: aging and tumor suppression.” Nucleic acids research 35.22 (2007): 7475-7484.

Rodier, Francis, and Judith Campisi. “Four faces of cellular senescence.” The Journal of cell biology 192.4 (2011): 547-556.

Salama, Rafik, et al. “Cellular senescence and its effector programs.” Genes & development 28.2 (2014): 99-114.

Tchkonia, Tamara, et al. “Cellular senescence and the senescent secretory phenotype: therapeutic opportunities.” The Journal of clinical investigation 123.123 (3) (2013): 966-972.

Zhu, Yi, et al. “The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs.” Aging cell (2015).

 

Updates on a Crowdfunded Mouse Lifespan Study – Article by Reason

Updates on a Crowdfunded Mouse Lifespan Study – Article by Reason

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The New Renaissance Hat
Reason
January 3, 2015
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For all that I think it isn’t an efficient path forward, one likely to produce meaningful results in moving the needle on human life spans, there is considerable interest in testing combinations of existing drugs and various dietary compounds in mice to see if healthy life is extended. I expect that as public interest grows in the prospects for aging research to move from being an investigative to an interventional field, wherein researchers are actively trying to treat aging, we’ll only see more of this. There is certainly a sizable portion of the research community who think that the the best path ahead is in fact the pharmaceutical path of drug discovery in search of ways to slightly slow the aging process. To their eyes slightly slowing the aging process is all that is plausible, and adding five healthy years to life by 2035 would be a grand success. Google’s Calico initiative looks set to take that path, for example, which I is why I’m not all that hopeful it will produce meaningful results in terms of healthy years gained and ways to help the old suffer less.

There is a considerable overlap between researchers aiming to gently slow aging via drug discovery and researchers whose primary motivation is still investigation, not intervention: to produce a complete catalog of metabolism and how it changes with age, and it’s someone else’s problem to actually use that data. So we have, for example, the Interventions Testing Program at the NIA. This program was long fought for by researchers tired of the lack of rigor in most mouse life span studies, and the people involved are essentially engaged in replacing a lot of carelessly optimistic past results with the realistic view that very little other than calorie restriction and exercise actually does reliably extend life in mice if you go about the studies carefully. This is good science, but it isn’t the road to extended human life spans: it instead has much more to do with understanding the process of aging at a very detailed level. That task is vast and will take a very long time even in this age of computing and biotechnology.

To my eyes the right way to go is the repair approach: build the biotechnologies needed to repair the forms of cellular and molecular damage produced as a side-effect of the normal operation of metabolism, and which clearly distinguish old tissues from young tissues. If you want rejuvenation of the old, a path to adding decades to healthy life, and to eliminate all age-related disease, then repair is the way to go. Fix the damage, don’t just tinker with the engines of life in ways that might possibly slow down damage accumulation just a little. This strategic direction can allow researchers to largely bypass the great complexity of the progression of aging and focus instead on fixing things that are already well known and well cataloged. But I say this a lot, and will continue to do so until more than just a small fraction of the research community agree with me.

Back to mice and lifespan studies: in this day and age institutional research is far from the only way to get things done. Early-stage research is becoming quite cheap as the tools of biotechnology improve, and the global economy allows quality scientific work to be performed in locations that are lot less expensive than the US or Western Europe. We have crowdfunding, the internet, and a supportive community, which means that any group of ambitious researchers can raise a few tens of thousands of dollars and set an established lab in the Ukraine to running a set of mouse lifespan studies. So that happened back in 2013, and has been ongoing since then despite the present geopolitical issues in that part of the world. It is perhaps worth noting that this is the same group that found no effect on longevity from transfusions of young blood plasma into old mice. The studies mentioned below used pre-aged mice, starting at old age as a way to try to discover effects more rapidly, an approach that is fairly widespread.

I am a little mouse and I want to live longer: updates

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Dear contributors, we wish you a happy New Year! We are sorry to be taken by a very-expected but very time-consuming c60 lifespan study to digest the data in a way to make the long report we had announced. So, for the New Year and in order for you not to wait longer, please find at least the main results so far:

1) 23 months old C57BL6 mice received a mixture of 6 therapies that had already been reported to extend the lifespan of mice: Aspirin; Everolimus (mTOR inhibitor, similar action as rapamycin); Metoprolol (beta blocker); Metformin (anti-diabetic drug); Simvastatin (lowers LDL cholesterol); Ramipril (ACE inhibitor).

The drugs were given in the food, at doses that had been reported to extend lifespan … when taken individually. Some people are given that combination of medicines so we hoped that the drug interaction would not be too damaging, and we had wondered if some lifespan synergy within some of these drugs could lead to an overall high lifespan (e.g. if the different drugs improve different functions). But we observed a lifespan reduction in males and in females.

2) In the food of some remaining females we mixed low doses of 4 medications against cardiovascular conditions: Simvastatin; Thiazide (lowers blood pressure); Losartan potassium (angiotensin receptor blocker, lowers blood pressure); Amlodipine (calcium channel blocker, lowers blood pressure).

The question was: taken at a low-to-medium dose, could these drugs that many aged persons take have some overall preventive effect? We transposed to mice an ongoing polypill clinical trial in the UK, using a basic human-mouse conversion scale. Again, a decrease in lifespan was observed.

3) Adaptations of the first combination of drugs actually extended lifespan!

We started at age 18 months instead of 23 months, reduced the dose (as a function of weight) and gave a) the 6 compounds b) ‘only’ aspirin+metformin+everolimus. The results are to be analysed in greater details as we haven’t analyzed the latest data yet. Also, whatever the refined analysis, we would already like to indicate that it would be good to reproduce the experiment in some other conditions, e.g. hybrid mice; in particular as the mortality rates of these mice was higher than the first series (but in a consistent way that supports the life extending effect).

4) Ongoing C60 experiments

After many difficulties in setting the experiment (cross-border transportation in current geopolitical times, checking absorption in mice/ detecting C60/correct source of C60, administration tried in food and replaced by gavage, training for gavage and various measures) we have transposed the popular lifespan test with c60 fullerenes reported in rats by Baati et al. to mice (CBA strain, common in the lab) and with more animals (N=17 per group). There are three groups (gavage of water, of olive oil, of C60 dissolved in olive oil), there are … a lot of health measures and a lot of gavage (at the beginnings of the experiment as administrations are first very frequent and then gradually less frequent). Given that the experiment starts with mid-aged animals, the results are expected for the beginning of 2016.

The original C60 results from a few years back were greeted with some skepticism in the research community, given the very large size of the effect claimed and the small number of animals tested. There was, I think, also a certain annoyance: now that someone had made what was on the face of it an unlikely claim of significant lifespan extension via administration of C60, then some other group was going to have to waste their time in disproving it. We’ll see how that all turns out, I suppose. This is science as it works in practice.

At some point the broad structural classes of research illustrated by the Interventions Testing Program and this crowdfunded mouse study will meet in the middle, and the process of funding and organizing scientific programs will be a far more complicated, dynamic, and public affair than is presently the case. I think this will be for the better. All that we have we owe to science, and a majority of the public thinks all too little of the work that will determine whether they live in good health or suffer and die a few decades from now. The more they can see what is going on, the better for all of us in the end, I think.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries. 
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This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.

Extending Life in Mice With Artificially Shortened Life Spans is Rarely Directly Relevant or Useful – Article by Reason

Extending Life in Mice With Artificially Shortened Life Spans is Rarely Directly Relevant or Useful – Article by Reason

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The New Renaissance Hat
Reason
May 4, 2014
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There are numerous examples of studies that use mice genetically engineered to suffer forms of shortened life span with the appearance of accelerated aging. One has to be very cautious in reading anything into this sort of work, however: it is rarely of any great relevance to normal aging, as it creates and then attempts to ameliorate an entirely artificial situation. The appearance of accelerated aging is not in fact accelerated aging, but is rather often caused by mechanisms that are of little importance in normal aging. Even when the mechanisms are relevant, the overall metabolic circumstances can render it impossible to determine whether or not a partial treatment will be of any use in normal aging. The gold standard for relevance when evaluating new methods is the extension of life in unmodified mice, but unfortunately this is expensive and slow.

The publicity materials quoted below are a good example of research in animals exhibiting shortened life spans. Here scientists are investigating a protein involved in the induction of cellular senescence. As is often the case, however, from the structure of the work it is impossible to tell whether or not their drug candidate will be of any use as a treatment to lower levels of cellular senescence in normal aging and thus produce benefits such as extended health and life span. Those tests will still have occur:

Quote:

When cells or tissue age – called senescence – they lose the ability to regenerate and secrete certain proteins, like a distinctive fingerprint. One of those proteins, PAI-1 (plasminogen activator inhibitor) has been [a focus of] research, originally as it relates to cardiovascular disease. “We made the intellectual leap between a marker of senescence and physiological aging. We asked is this marker for cell aging one of the drivers or mechanisms of rapid physiological aging?”

For the study, [researchers] used mice bred to be deficient in a gene (Klotho) that suppresses aging. These mice exhibit accelerated aging in the form of arteriosclerosis, neurodegeneration, osteoporosis and emphysema and have much shorter life spans than regular mice. [These] rapidly aging mice produce increased levels of PAI-1 in their blood and tissue.

Then scientists fed the rapidly aging mice TM5441 – the experimental drug – in their food every day. The result was a decrease in PAI-1 activity, which quadrupled the mice’s life span and kept their organs healthy and functioning. “This is a completely different target and different drug than anything else being investigated for potential effects in prolonging life. It makes sense that this might be one component of a cocktail of drugs or supplements that a person might take in the future to extend their healthy life.”

Link: http://www.northwestern.edu/newscenter/stories/2014/04/experimental-drug-prolongs-life

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries. 
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This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.

The Methuselah Mouse Prize: Changing the Conversation about Aging – Article by Advocate of Negligible Senescence

The Methuselah Mouse Prize: Changing the Conversation about Aging – Article by Advocate of Negligible Senescence

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The New Renaissance Hat
Advocate of Negligible Senescence
May 3, 2014
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ANS_Methuselah_Mouse_Prize
Methuselah Foundation created a stir in the research community by introducing the Methuselah Mouse Prize in 2003. The Mouse Prize was designed to directly accelerate the development of revolutionary new life extension therapies by awarding two cash prizes: one to the research team that broke the world record for the oldest-ever mouse; and one to the team that developed the most successful late-onset rejuvenation strategy.Unlike other engineering prizes (for example, the X Prize for lunar exploration), an award of the Methuselah Mouse Prize is not the end of the matter. The winner establishes a record that others have to break.
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Why mice? Mice are genetically similar to humans. They are small and inexpensive to maintain so studying large quantities is feasible. Their short lifespan, about three years, makes it possible to see if interventions result in longer, healthier lives—all in time to be of benefit to our own lives.

The Mouse Prize for longevity was first won by a team led by Dr. Andrzej Bartke of Southern Illinois University. The prize for rejuvenation first went to Dr. Stephen Spindler of the University of California.

Additionally, in 2009, the first Special Mprize Lifespan Achievement Award went to Dr. Z. Dave Sharp for the successful healthy life extension of already aged mice using a pharmaceutical, rapamycin.
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Through programs like the Methuselah Mouse Prize, Methuselah Foundation has helped change the conversation on aging and longevity, lending credibility and prestige to areas of research that once were openly frowned upon.
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Previous winners have already proven that healthy life can be extended; more wins are possible by researchers who can best previous winners’ performances, and each new winner pushes the outer limits of healthy life back even further.

How translatable the lesson of a Methuselah mouse will be to people is a matter of debate. The logic of disposable-soma theory applies to both species.

Private donations made since 2003 have bumped the prize value up to nearly $3.5 million, according to the latest update on the Methuselah Foundation website.

Don’t be misled by the size of the fund into thinking that a small donation will make no difference, because this is fundamentally a popular enterprise, a people’s prize, so the number of individual donors is really just as important as the total.

Searching for a cure for age-related ill health, a problem that kills more people than all other causes combined, is a moral imperative. The Advocate for Negligible Senescence publishes articles that discuss and educate the public about research to combat senescence. See the Advocate’s Facebook page.