Part 2 of 2 of the Draft of H. sapiens 2.0 (2015)[May 25, 2014].

"Nature Creates Life on Earth with Aging as a Side Effect"

Exclusively based on Darwinian-fitness/survival criteria, Nature -- in her attempts [*] to create sustain life on Earth over the past 3.8 BY (billion years) by constantly stirring the pot has accomplished a great deal in that time. She created complex sets of ecologies, each with dynamic food chains/webs from tiny prokaryotic bacteria to multicellular creatures 10 m tall comprised of 100 billion adult cells (with over 200 histologically different tissue types) each cell with a nucleus and chromosomes within each containing digital instructions for the recapitulation of the entire creature in the form of double-helical sequences of nucleotides that we call DNA. The zipper architecture of the rungs of the helix in conjunction with histone proteins and methyl groups that decorate the DNA (epigenetics) make it possible for Nature to achieve reasonably precise cellular replications to take place with the aid of enzymatic proteins as subsequent exquisitely-timed mitotic divisions yield complex tissue types during the process of embryogenesis starting from a single cell, as suggested by Watson and Crick in their famous 1953 paper in Nature [James D. Watson and Francis H. C. Crick, "Genetical Implications of the Structure of Deoxyribonucleic Acid" Nature, Vol. 171, No. 4361, pp. 964-7 (May 30, 1953)]. Subsequences of DNA (genes) were then compiled into genomic networks as subroutines that, when properly packaged, were conserved over millions of species because they were functionally useful for the survival of a wide variety of creatures, such as the gene networks that control metabolism or the networks that allow for synergism with an E-coli microbiome.

About 200 KYA (thousand years ago) humans (H. sapiens 1.0) arrived on the scene, inheriting a complex set of machinery from our mammalian ancestors (and their warm-blooded multicellular predecessors, many of whom are extinct in our modern times). The complexity of the machine is so sweeping and difficult for us to comprehend because the dynamic range of objects Nature rearranged extends over 11 orders of magnitude from the linear dimensions of atoms (0.1 nm) and molecules ([10 - 100] nm) to dinosaurs (10 m). These objects or building blocks at Nature's disposal are for the most part invisible to the human eye, so how could we be expected to know about them or to manipulate them for our own purposes? It's been less than 500 years since engineers provided us with the optical technology and microscopes to achieve a resolution of microns (bacteria or active human sperm with curiously long wiggling tails originally thought to be a parasite) and less than 60 years since we could appreciate the molecular infrastructure of organelles within cells let alone DNA, RNA, and protein molecules.

* The word "attempts" personifies Nature as though she had a teleological agenda or purpose (with an objective function subject to various constraints) when in fact this reification may be totally false. To speak of her as "she," as though there were some sort of intentionality or "will" at play, may be as silly as saying that "golf balls roll down hills because of their desire to find a good resting spot." Golf balls do not have a will, even though human golfers may wish for them to roll closer to the hole. Nature plays a game of chance in the same way that a roulette wheel does in a casino. If Nature is nothing more than a stochastic process obeying random time-dependent distributions and laws of probability with the solar system serving as casino, why would it be necessary to personify her linguistically (as a person with goals, objectives, or purposes) any more than one needs to personify the laws of physics, like saying gravity "desires" all golf balls to roll down hill? Well, the reason is one of convenience and parsimony of writing. Therefore, anytime I speak metaphorically of Nature as a person, using English verbs normally reserved for autonomous agents, you should substitute in your mind the more awkward phrase "stochastic process." We will discuss this topic in more detail later when we discuss Prof. Richard Dawkin's "Theory of Agency." [xx1]

Ref.: xx1

Why are humans so anthropocentric? That is to ask, why are we so pretentious? We seem to see ghosts and gremlins behind every tree where there may be darkness or mystery but really only the sound of the wind blowing through the leaves. Prof. Richard Dawkins of Oxford University has now provided us with a "Theory of Agency" to explain this strange phenomenon of a teleological imperative that we can use to comprehend why we incorrectly imagine that even rocks have an internal purpose or intent based on some sort of "Grand Design" or what others have called "Intelligent Design," which strikes me as an oxymoron, since there seems little about the world that ought to be considered "intelligent." Are rocks agents with intent? Is the wind an agent and not just an other random stochastic process (chosen from a mathematical distribution)? Indeed, if we do hear a rustling in the leaves behind us and choose to ignore it, it could instead be a stealthy predator that has in mind to eat us for lunch or alternatively it could be merely the wind after all. Or course, there are Type-I and Type-II errors associated with decisions for each case. Once you decide that it's important as a child to obey your parents instructions, like "Don't pick up snakes," paranoia becomes a legitimate way of navigating your life's trajectory as soon as you find out that there really are creatures that will team up to eat you for lunch. Soon, you come to appreciate that a teleological model of the world is necessary for survival once your parents are no longer around, and you begin to invent God, a Divine Designer, whose intent was "to make you in His image." This is the foundation for the Theory of Agency. Obviously, attributing intent to other humans (especially strangers) becomes critical as time goes on, since humans are the most dangerous creatures on the planet when it comes to exploitation of scarce resources and you happen to be in the way of this other human tribe.

Our challenge then is to figure out how this incredibly complex machine works all the way down to the atomic/molecular level so we could design and configure it more to our liking, especially whenever it breaks down (disease), in the same way that classic-car hobbyists repair and keep their cars licensed to drive on freeways to attend auto shows long after the manufacturers' warranty periods have expired. Furthermore, we need to do this in our mutual life times, if it is to help us personally.

Humans longed for the ability to fly for millennia, as they enviously watched birds fly, seemingly effortlessly. Leonardo da Vinci's notebooks (~1500) teach us something about what would be needed to build an autonomous heavier-than-air flying machine, but he was far ahead of his time in terms of practical implementation, and, of course, modern aircraft don't flap their wings.

The Wright Brothers actually built the first wind tunnel to tease out the empirical data needed to add an engine to a glider and make it fly under the right wind conditions (> 20 mph), which took several days of waiting. The inaugural flight took place on December 17, 1903 and lasted only 12 seconds (distance = 120 feet). In 1904, the Wrights continued refining their designs and piloting techniques in order to obtain fully-controlled flight. Major progress toward this goal was achieved with a new Flyer in 1904 and even more decisively in 1905 with a third Flyer, in which Wilbur made a 39-minute, 24-mile nonstop circling flight on October 5th. Sadly, an accurate replica did not fly during a celebration of their 100th anniversary at Kitty Hawk, NC for then President George Bush, since the wind conditions weren't quite right and the engine didn't have sufficient horse power, even after several attempts (December 2003). So we can only conclude that the human dream of flight was a non-trivial business and luck played a substantial role.

Wright Glider, 1901 Wright Flier,1903

Ironically, today's airplane passengers take international air travel for granted. Will there ever be a day when we take "biological immortality" for granted?

Because the Wrights figured out flying even before there was a discipline called aeronautical engineering with the underlying integral calculus and differential equations to distinguish smooth (Laminar) from turbulent air flow, doesn't mean that there can't be "biogerontological brothers" who can similarly achieve the equivalent (with autologous, pristine stem-cell therapies and genetic engineering) even without fully understanding Nature's mechanisms for creating a complete life history for each-and-every creature, large-and-small, living upon the Earth. Our answer should be a resounding "Yes, we can."

We must now ask if it is finally time to examine our assumptions that The Grim Reaper
Grim Reaper
is waiting in the wings for each and every one of us, indefinitely into all future generations. That's preposterous; the very idea is absurd! A major purpose of this book is to disabuse anyone of the fiction your parents taught you when you were a child - - what was taught to them by your grandparents - - that the very idea of immortality is impossible in principle just because it's never been done before.

What is Life?

When Edwin Schrodinger, German Nobel Prize Winner in Physics, was asked to give a formal lecture in 1927 on the topic of "What is life?" at the University of Dublin, the idea that life followed the Laws of Physics (in particular the Second Law of Thermodynamics [Entopy]) was not particularly fashionable, even among scientists or other cognocenti. For ordinary folk, even theologians, vitalism (magical thinking) prevailed. The temptation to insist on a "designer" was overwhelming, since that explanation fit all the fact of the time. Now we know that Prof. Schrodinger was right. Life is not an exception to the Laws of Physics in any way. A modestly revised definition of life is the following ...
Life is a recursive set of stochastic subroutines that are expressed in a complex, non- linear fashion in a procedural language built up out of five alphabetic nucleotides, physically realized in DNA and RNA as {A, T, C, G, and U}. In short, life is a chemical computer program that executes in a bath of organic ingredients that goes through a number of phases for complex, multicellular organisms, including (1) embryogeneis; (2) development; (3) reproduction; and (4) senescence. As one example for flowering plants, the program must pass through the following nine phases: {fertilized seeding, sprouting, rooting (for water), stemming, leafing (photosynthesis using chlorophyl and sunlight}, budding, blooming, formation of species' specific phenotypes like flower morphology, fragrance, and color that serve to exploit willing pollinators (birds or bees), even fruiting with edible seeds in the interior for larger creatures to defecate at a greater distance than would normally be feasible by wind alone, followed finally by wilting and rotting. (assuming "Mission Accomplished," flowering plants must survive the annual seasons associated with the planet's revolution around the sun and reboot in the Spring.) This definition is not only consistent with the Laws of Physics but also Darwinian Evolution that further explains how this vast array of plant and animal phenotypes arrived on the planet up-and-down the phylogenetic chain (web) where most of the tree branches were already trimmed long before our arrival on scene. This complexity even confused a genius like Sir Isaac Newton; even though he invented the calculus, he didn't invent the Mathematical Laws of Probability and Statistics that would come later, and he was a little before his time. Indeed, our culture have a long way to go to appreciate these Laws (Monte Carlo style stochastic processes) despite the common presence of Lotto Games and Casinos that give away free parking in Las Vegas, which dupes willing gamblers into the belief that if they are on a winning streak this must be their lucky day. The only difference with evolution is that the "house" has been playing its game for nearly four billion years. It built dopamine as a neurotransmitter in our brains for its own nefarious purposes (orgasims to ensure survival of the species, so that we could happily execute our biological imperative to "Go forth and mulitply"), assuming the presence of a willing partner.

Along with the definition of life, it is useful to define the notion of a cell. A biological cell has the characteristics of a small city whether it's eukaryotic (having a nucleus) or procaryotic (without a nucleus)... There is a huge library building right in the middle called the Nucleus. There are power plants called Mitochondria, highways called Microtubules and Actin Filaments. There are city walls (Membranes), post offices (Golgi Apparatus), Ribosomes for manufacturing, and many other structures each with their unique purpose (e.g., RER {Rough Endoplasmic Reticulum} and SER{Smooth Endoplasmic Reticulum}) [3]. For long axons in neurons these microtubules are essential to transfer neurotransmitters from their point of synthesis to their synaptic endpoints where they're most needed.

Ref.: 3. Peter M. Hoffmann, Life's Ratchet: How Molecular Machines Extract Order from Chaos (p.169; Basic Books, New York; 2012).

The Life History of a multicellular reproductive organism, including humans can be expressed mathematically as a tripartite linear spline function of a graph with abscissa in units of time ["years" in the case of mammals] and ordinate in units of "fitness" [*] of the form ...
y = Ax, where

vector y = [y1
y3] and

vector x = [x1

and the 3x6 matrix A =

[m1, b1, x11, y11, x21, y21 where x11 = -0.75 and y11=0 by definition
m2, b2, x12, y12, x22, y22 where m2<0
m3, b3, x13, y13, x23, y23 where x23 = 122 yo [J.C.] and y23 = 0 fitness by the definition of Death]

This defines three straight lines of the form y = mx + b (See Figures 1 and 2) where the cut- off points are in a epsilon neighborhood of a triple integral Gaussian function with mu and sigma defined so that we can allow for a little bit of slop in their end points as the lines intersect. Think of a Normal function N(0,1) rotated or spun 360 degrees in the third dimension, referred to as the "Designed Ground Zero" or DGZ in weapons analysis where there is a CEP (Circular Error Probability) [could be elliptical rather than circular if the bomb is dropped from a moving platform rather than a missile that hits the ground in a perpendicular fashion or an environment with high wind shear] that an actual weapon will hit its intended ground target within a certain error [bull's eye]).

We call the first phase development. This is in context of oocyte fertilization, embyogeneis, fetogenesis, birth, infancy, adolescence, up to and including puberty as defined for humans (both genders) as mu = 12 yo with a standard deviation of ~2 years.

We call the second phase reproductive potential. It terminates in menopause for females and andropause for males.

We call the third and final phase senescence. It terminates in death, the point at which fitness again becomes zero, by definition.

One can distinguish at least three types of fitness functions that could be used to explain the clinical aging process in the third phase:
1. A polynomial function of subsytem fitness (for example, FEV-1 for the Respiratory System)
2. A polynomial function of a dozen significant physiological parameters that also measure biomarkers of fitness, such as grip strength.
3. A polynomial function of four laboratory protein markers as measured in blood serum(?):
{alpha} x albumin + {beta} x Alpha-1-Acid Glycoprotein + {gamma} x Citrate + {delta} x Particle Size of VLDL [Very Low Density Lipoprotein]}[ref.] Interestingly, based on independent work by Estonian and Finnish researchers, those individuals with a score in the top 20 percent had a risk of dying in five years that was 19x greater than that of individuals in the bottom 20 percent (288 vs. 15 deaths) independently of well-known risk factors, such as age, smoking, drinking, obesity, high blood pressure, and elevated cholesterol.

Clearance of Senescent Cells Following Transplantation

April 29, 2014; Cellular senescence became a critical topic in aging research following work done at the Mayo Clinic [xx2] in which control mice died on cue but genetically modified mice from the same cohort lived much longer. As the number of senescent cells increases with age due to an accumulation of random mutations in the DNA of their nucleii, they consume resources (oxygen and food calories) but cease to contribute to the function of their local tissue. Furthermore, they may cause potential harm to the normal cells surrounding them through the production of signaling proteins or growth factors that travel through in the adjacent Extra Cellular Matrix (ECM). The cancer research community will soon be able to expunge these wayward cells even without prior genetic modification; however, using the tools now under development by modern oncologists with the aim of triggering apoptosis in cancer cells and minimal side effects may not work. But there may also be other ways to trigger Programmed Cell Death (PCD) in senescent cells. A research result by Italian researchers [Ref 2] that was published earlier this year (2014) and makes for an interesting companion piece to other more recently published papers in which researchers showed that a method of growing large numbers of liver cells (hepatocytes) via serial transplantation in mice can reverse cellular senescence as a bonus. So cancer researchers have found that cells transplanted into rats have a similar effect, at least for cellular senescence that is artificially induced via the introduction of a mild toxin that causes DNA damage and other cellular dysfunction leading to cancer. Nevertheless, we would need to observe a similar result in older animals with natural levels of cellular senescence before assuming that this could become a valid intervention step in the aging process itself.

Ref. xx2.: "Clearance of Senescent Hepatocytes in a Neoplastic-Prone Microenvironment Delays the Emergence of Hepatocellular Carcinoma"
Fabio Marongiu, Maria Paola Serra, Marcella Sini, Fabrizio Angius, and Ezio Laconi

Potential Chapter Quotes:

(On September 17, 1994, Alabama's Heather Whitestone was selected as Miss America 1995.)

Question: If you could live forever, would you and why?

Answer: "I would not live forever, because we should not live forever, because if we were supposed to live forever, then we would live forever, but we cannot live forever, which is why I would not live forever," - - Miss Alabama in the 1994 Miss USA contest.

"In Tooth and Fang." - - Thomas Hobbs

Who trusted God was love indeed
And love Creation's final law
Tho' Nature, red in tooth and claw
With ravine, shriek'd against his creed.
-- Alfred Lord Tennyson's In Memoriam A. H. H. (1850).

Life is an ecosystem of creatures both large and small that will eat you either from the outside in or from the inside out (parasites).

Insert quote on Vitalism, Craig Venter, p. 109.

Brain, Map, Fetus...

US National Military Academies:

Army: West Point
Navy: Annapolis
Air Force: Colorado Springs
At the Graduate Level: National Defense University (Washington, D.C.)

I enrolled in Air Force ROTC at RPI (1958) for one semester and then dropped out.

"In the coming decades, I can envision that we will witness many extraordinary developments of tangible value, such as ... customized human stem cells to regenerate a damaged, old, or sick body... rejuvenating worn-out muscles, and so on." - - J. Craig Venter, p. 158, Life at the Speed of Light (Viking, New York; 2013).

"What I cannot create, I do not understand." (Found written on his blackboard at the time of his death in February 1988) - - Richard Feynman, Ph.D., CalTech Nobel Prize in Physics for his development of Quantum Electrodynamics.

More and more of the world's population is moving away from a reliance on God as a way of dealing with our human condition (mortality), i.e., seeking comfort in prayer and religion as the Grim Reaper quietly approaches. Irreligion (atheism and agnosticism) is the fastest growing "faith" in the world. ["World without God," New Scientist (May 2, 2014)]. Will we eventually see a world without God? Indeed, such a world could turn out to be a much better place unburdened by the absolutist need for one religion to dominate all others by force (or war) if necessary. But our desire to play God by seeking to intervene in the aging process at the most basic biological (molecular) level, and not just through cosmetics or plastic surgery, leads to a seeming conflict between life-extension-science and religion (mutually antagonistic paths to redemption/salvation). This hubris/ambition may ultimately lead us to be punished for our failure to gratefully accept the status quo to which we did not provide informed consent. But this need not be so, if there is a middle ground.
Francis S. Collins, The Language of God: A Scientist Presents Evidence for Belief, (Free Press; Simon and Schuster, New York; 2006).
Dr. Collins argues that science and religion need not be hostile antagonists. Even though Collins, now head of NIH, is at the cutting edge of the study of DNA - - the code of life - - he maintains an unshakable faith in God and scripture and makes the case that God and science can coexist harmoniously. Indeed, if at a future time we were able to fully understand the stochastic forces that operate on DNA (by random mutation) followed by "survival of the fittest of each species" and chose to call those forces "god," I would be perfectly comfortable with that naming. By the way, church-going religions provide many other advantages of social networking that are valuable for longevity beyond the belief in an omniscient, ubiquitous, omnipotent being with a mysterious personal agenda. If we were to abandon our need to attribute an agenda to God, we're half way there.

"I was bold in the pursuit of knowledge, never fearing to follow truth and reason to whatever results they led, and bearding every authority which stood in their way." - - Thomas Jefferson

Get a quote of the form ... "Light a candle in the darkness." - - Carl Sagan

"As the [racing bike] riders do not stop short as they reach the finish line. There's a little finishing canter [slope] before coming to a standstill. There's no time to hear the kind words of friends or to say to one's self, The work is done.' But just as one says that, the answer comes back, The race is over, but the work is never done while the power to work remains.' The canter that brings you to a standstill need not be the only cause that brings you to a rest. It cannot be while [your brain] is still alive. For, to live is to function. That is all that living is."
- - Oliver Wendell Holmes, "Radio Address (1931)" on the occasion of his 90th birthday, in Richard A. Posner, Ed. (1992).

"How dull it is to pause, to make an end;
To rust unburnished, not to shine in use!
As though to breathe were to live."
- - Ulysses by Tennyson

"Once the executable portion of our DNA code has run out of new and interesting things to do, it appears to be futile to attempt to disabuse ordinary people that ignoring the relentless, inexorable nature of the aging process (at an exponential rate with chronological age) will not lead to their permanent death (eternal oblivion). Ordinary people by that time are too busy contemplating the blissful paradise that is alleged to follow the sad event of their demise. Our clergy as well as our life-insurance brokers have their own agenda. They have been preaching or marketing/advertising respectively to our great-grandparents, our grandparents, our parents, our aunts and uncles, our cousins, our children, our neighbors for so long as to make any correction to this antediluvian path of thinking follow the quote from the Borg in Star Trek Resistance is futile!' This seems to be the operative form of current thought. Fortunately, our GRG Group does not agree."
- - Steve Coles (May 14, 2014).

"It is neither the strongest nor the smartest species that survives. It is the species that is most adaptable that survives." -- Charles Darwin

A few references on GDF-11 from NEJM Journal Watch...
It appears that there are at least 15 such growth factors [1].
Ref.: 1.
- Blood of young mice contains substances that reverse aging processes in heart muscle, skeletal muscle, and brain;
- One of these substances is a protein called Growth Differentiation Factor (GDF-11).
1. Sinha, M., et al., "Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle" Science 2014 May 9; 344:649. PMID: 24797481
2. Katsimpardi, L., et al., "Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors" Science 2014 May 9; 344:630. ( PMID: 24797482
3. Villeda, S.A., et al., "Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice" Nature Medicine 2014 May 4 PMID: 24793238

Much more to come.