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. . . and knowledge, as Lord Bacon observes, being power, the human powers will, in fact, be enlarged(ref); nature, including both its materials, and its laws, will be more at our command; men will make their situation in this world abundantly more easy and comfortable; they will probably prolong their existence in it. Get a copy here - Preview-Joseph Priestley Purchase a copy here.

 

The rapid progress true science now makes, occasions my regretting that I was born so soon.  It is impossible to imagine the height to which may be carried , in a thousand years, the power of man over matter.  We may perhaps learn to deprive large masses of their gravity, and give them absolute levity, for the sake of easy transport.  Agriculture may diminish its labor and double its produce; all diseases may by sure means be prevented or cured, not excepting old age, and lives lengthened at pleasure even beyond the antediluvian standardBenjamin Franklin

 

Genes define the limits of individual and specie lifespan.  We can accelerate aging with a variety of bad habits and risky behavior.  If we intend to live beyond antediluvian standards, genetic engineering is ultimately required. Caleb Finch prefaced Longevity, Senescence and the Genome with:

A major conclusion is that mechanisms by which genes influence lifespan and the particulars of senescence can be identified in some organisms. Many examples show an important role of alternative gene expression or of changes in gene activity as underlying causes of differences in lifespans between related organisms.  Other examples indicate changes in the genome itself, for which the best examples are somaticD cell chromosomal abnormalities.  However, these mechanisms in most other species remain obscure. From the vantage of our present scant knowledge, genomic mechanisms in senescence appear much more complex and phyletically diverse than genetic mechanisms in development.  So far no new biological mechanisms are yet required to account for senescence beyond those which operate during development or in pathogenesis during the early adult years.  Moreover there is an impressive number of examples of molecular and cell functions that remain unimpaired during long lifespans.  The conclusion from developmental biology that most somatic cells of young adults are genetically totipotent may provisionally be extended to later ages.  If so, many aspects of senescence should be strongly modifiable by interventions at the level of gene expression.  The proposal is supported by modifications of senescence through manipulations of the external or internal (physiological) environments.   Caleb Finch

The science relevant to our pursuit of immortality is summarized below.

 

Telomerase In order for cells to divide, the large DNA molecules that constitute genes (that linked together are chromosomes) must be duplicated (replicated). This service is performed by an enzyme called DNA Polymerase.  For technical reasons, DNA Polymerase cannot replicate the short segment of DNA on which it begins.  That means that each duplicated chromosome is a segment shorter than its immediate predecessor.  

 

At some point this progressive segmental loss of length interferes with cell function and further cell division – aka, senescence.  Telomerase functions to add length to chromosomes in egg cells (and unfortunately, cancer cells) reconstituting the normal length of individual chromosomes.  Sometime during embryonic development, production of telomerase is ‘turned off.’  Organisms with short telomeres live shorter lives on average than those with long telomeres; that is true among human beings as well.  (In the presence of telomerase even short telomeres remain functional, so length is not identical to function.)

 

Telomerase is the basis of Michael Fossel's book Reversing Human Aging :

This book is a promise and a warning.  It is a promise of a time when we will live longer and much healthier lives - of one hundred, two hundred, possibly five hundred years. . . We will be able to prevent, even reverse, aging within two decades. At the same time we will cure most of the diseases that now frighten and destroy usMichael Fossel

"Transfection" of cells with a retrovirus containing the human telomerase reverse transcriptase h(TERT) maintains telomere length and effectively gives normal cells an unlimited life span.  One obvious strategy is to ‘turn on’ the production of telomerase periodically to reconstitute chromosome length; then, after an appropriate period, turn telomerase off.  Geron Corporation[A] is pursuing telomerase with that end in mind. See Human Ageing and Telomeres by Calvin B. Harley, chief Science Officer for Geron.

 

Mitochondria
Mitochondria are intracellular organelles where fatty acids and sugars are processed to generate ATP. ATP (Adenosine Tri-Phosphate) is the energy currency of all living cells, driving the chemistry of life.  With age, mitochondria become progressively less efficient at generating ATP (perhaps accounting for the declining sense of "energy" with age).   The free radical theory of aging posits that aging is a consequence of cumulative damage to cellular machinery, especially mitochondria, caused by free radicals.

 

Free radicalsD are generated in the process of metabolizing sugars and fats to generate ATP in mitochondria (called oxidative phosphorylation).  Living cells are not defenseless against this damage, they produce a variety of enzymesN that neutralize free radicals.  The concentration of protective enzymes in a given species is directly proportional to their respective lifespans, which inspires the search for natural anti-oxidants.  Severe calorie-restricted diets are known to add 30 - 50% to the lifespan of mice. In an ongoing study, Rhesus monkeys on calorie-restricted (CR) diets are dying at half the rate of controls. This is a universal phenomenon, right down to yeast. The effect has been correlated with oxygen free radicals. However, yeast grown in an abundance of glucose, incompletely metabolize it to alcohol using one metabolic pathway. In relative scarcity, glucose is completely metabolized to CO2 in a second pathway. When scientistsN manipulate yeast and force them to use the second metabolic pathway despite an abundance of glucose, the effect on longevity was the same as CR. The implications are clear, we may not need to starve to live longer. Further, this "CR effect" in yeast is dependent upon SIR2p, "a protein that ups the number of times a yeast cell divides. It confers this perseverance by its ability to 'silence' chromosomal regions, a process that shuts off genes and prevents cellular machinery from cutting and pasting DNA together in new and often troublesome ways." 

Speculating further: the mother is the source of mitochondria in a newborn infant. However. the infant's mitochondria are substantially more efficient than the mother's.  Were maternal mitochondria rejuvenated during oogenesis?D   If so, could this rejuvenation process be commandeered to rejuvenate mitochondria in the somatic cells of an 75 year old man?  Germane to this question is the disposable soma theoryB that hypothesizes a bioeconomic decision-making model  wherein resources (i.e., energy) are allocated between germ cells and somatic cells, in response to evolutionary pressure.  The more resources dedicated to maintaining somatic cells, the longer the organism lives.  However, accidents, disease, predators, etc., coupled with the general principle of diminishing returns, makes a large investment in immortal somatic cells impractical, given that the reproductive process requires major investment of resources.  

 

Germ cell lines are immortal, so mechanisms must exist to prevent aging.  If there is a process of mitochondrial rejuvenation during oogenesis, the disposable soma theory suggests it may be difficult to enlist in the service of somatic cells.

 

Nanotechnology
The somatic mutation theory of aging proposes that aging is a consequence of cumulative damage of DNA by environmental and endogenous toxins, causing progressive dysfunction or non-function of genes - essentially an expansion of the free-radical theory to include exogenous toxins.  How would this cumulative damage be remedied?  The answer may be cell repair machines proposed by Erik Drexler:

 

Cell repair machines will be comparable in size to bacteria and viruses, but their more compact parts will allow them to be more complex. they will travel through tissue as white blood cells do, and enter cells as viruses do - or they could open and close cell membranes with a surgeons care. Inside a cell, a repair machine will first size up the situation by examining the cell's contents and activity, and then take action. Early cell repair machines will be highly specialized, able to recognize and correct only a single type of molecular disorder, such as an enzyme deficiency or a form of DNA damage. Later machines (but not much later, with advanced technical AI systems doing the design work) will be programmed with more general abilities.  K. Erik Drexler

That was 1986. Currently, the only nano-manufacturing is done by ribosomes - there are no substantial nano-machines.  How long will it take to develop cell repair nano-technology?  According to Drexler, 17 years - 2018AD.  Other estimates vary from 2010 to 2050.B

 

Reversible Biostasis: Cryobiology
If the technology will not arrive in time to save us, what then?  Cryobiology may offer an alternative.  Polar marine fish have anti-freeze proteins.  Caterpillars of the gall moth have body fluids that are 40 percent glycerol in midwinter, representing 19 percent of the total body weight of the animal that allows the insects to supercool to -38 degrees C.

 

Certain species of frogs survive repetitive freezing and thawing during the winter. In frogs, glucose functions as a cryoprotectant.   With freezing there is rapid synthesis of glucose from glycogen, generating serum glucose levels of 4500 mg/dl (45 times normal human levels), 

 

Identifying glucose as the mystery cryoprotectant was only the first step.  In the years that followed, Dr. Storey has also isolated more than 20 genes out of the 10,000 in frog chromosomes that are turned on when the animal starts to freeze.  It appears those genes shut down the frog's metabolism and pack its cells with sugar.  The idea is to get those same genes working in human organs.   "Here is the joy of biochemistry.  The basic structure and function of all cells of all vertebrates are the same.  You have the same type enzymes and proteins as a frog and a fish.  You have genes of similar sequence and you have the same control of genes over all.  All you have to do is learn what genes and enzymes to regulate, then learn how to turn them on or off.  All we have to do is learn to twiddle them," Dr. Storey said.  He has a jumpy, manic energy, explaining that his field is called cryobiology, which differs from cryonics, the practice of preserving the whole body, head, or brain of persons recently declared legally dead, in the hope of revival at some time in the future. Cryonics is on the scientific fringe, and not largely accepted by the research community.  Cryobiology, on the other hand, gets significant government funding and provides insight into how living cells work. Anne McIlroy

One might speculate whether cryonics would be "on the scientific fringe, and not largely accepted by the research community" if researchers received "significant government funding."   It appears that successful reversible biostasis would be dependent upon mastering a process of gene insertions into somatic cells calibrated to deliver a cascade of biochemical events controlled by drugs, such that human beings may be preserved for later technologies that promise them health and longevity.

 

Genetic Engineering What is the state of the art for genetic engineering?

Insertion of genes by viral vectors, liposomes.  Where does genetic material inserted into cells end up? Is it incorporated into a specific chromosome based upon its DNA sequence, randomly inserted into chromosomes, or catabolized?

Does there exist the ability to excise targeted genes? If genes could be inserted in targeted cells, turned on, off or otherwise manipulated with drugs, and later deleted, you might accomplish much that was intended for Drexler's cell repair germ.

 

Xenotransplantation

 

Stem Cells & Tissue Engineering


Glycosylation of proteins
Human cells are bathed in serum that contains 1mg/cc of glucose. Over time cells and structural proteins are "glazed" with this sugar.  This process entails cross-linking of proteins by glucose, which is thought to reduce elasticity and function.  It is thought to account, in part, for hypertension and plays a role in the accelerated senescence of various organ systems in diabetics.  There is a research drug (ALT-711), currently being studied in a clinical trial for therapy of hypertension.   The drug is an analog of thiamine, that breaks the glucose cross-links.  The fact that it reduces blood pressure over time, suggests that it is restoring the native elasticity of arteries. 

 

A.G.E. Crosslink Breakers
Advanced Glycosylation End-products (A.G.E.s) are permanent glucose structures that form when glucose binds to the surface of proteins. Many of these proteins, including structural proteins such as collagen and elastin, play an integral role in the maintenance of cardiovascular elasticity function and vascular wall integrity. Diabetic individuals form excessive amounts of A.G.E.s earlier in life than non-diabetic individuals. This process can impair the normal function of organs that depend on flexibility for normal function, such as blood vessels and cardiac muscle. The formation of A.G.E. Crosslinks leads to increased stiffness of tissues, abnormal protein accumulation and organ dysfunction, which together cause many of the complications of aging and diabetes. Loss of flexibility of the vasculature leads to isolated systolic hypertension, which creates increased workload for the heart and may lead to myocardial hypertrophy and heart failure.

AlagebriumN is the first in the A.G.E. Crosslink Breaker class that has been shown to reverse or “break” A.G.E. crosslinking, thereby restoring more normal function to organs and tissues that have lost flexibility. Pharmacologic intervention with Alagebrium1 directly targets the biochemical pathway leading to the stiffness of the cardiovascular system. Its mechanism of action is new and novel, and is unrelated to that of any pharmaceutical agent either currently prescribed or in clinical development. Importantly, Alagebrium does not disrupt the natural enzymatic glycosylation sites or peptide bonds that are responsible for maintaining the normal integrity of the collagen chain. Thus, normal structure and function is preserved while abnormal crosslinking is reduced. 

 

Pace of change
Nixon launched the "War on Cancer" in the early '70s, yet we still use toxic drugs that kill tumors only slightly faster than the patient.  AIDS has been an epidemic for 20 years, yet no vaccine.  Fusion power plants have yet to materialize despite the promise of 50 years ago, . . . and so on.    Prediction is fraught with hazard "especially about the future."  Consider this quote from 1997:

Perhaps the most pivotal and controversial of all the divisions of the NIH is the Human Genome Project (officially the National Center for Human Genome Research), one of the most ambitious projects in medical history, a $3 billion crash program to locate all the genes within the human body by 2005.   Michio Kaku

Three years later in Barron's,B  

An international consortium, the Human Genome Project, and Celera Genomics Group announced jointly they have each roughly deciphered the genetic code that houses the blueprint for the human organism. Francis Collins, director of the consortium, called the map a first glimpse of the instruction book previously known only to God.

Some things do happen ahead of schedule.

Apoptosis
Signal transduction
Neurobiology
Cell Stress Biology
Cytokines, Growth Factors and Hormones
Immune Cell Function Tissue Engineering>
Vaccine Production
Gene Therapy
Cytogenetics
High Throughput Screening
Drug Discovery & Combinatorial Chemistry
Drug Delivery
PCR
Nucleic Acid Purification
Automated DNA Sequencing>
Recombinant Protein Expression and Purification
InVitro Transcription and Translation
Nucleic Acid Electrophoresis
Gene Expression
Nucleic Acid Labeling, Hybridization and Deletion
Cloning
Custom DNA Synthesis
Custom Peptide and Antisera Services

 

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