[Hplusroadmap] Fwd: Re: [GRG] NewAbs: Mouse Skin Rejuvenation with NF-kappa-B

[Bryan Bishop]

----------  Forwarded Message  ----------

Subject: Re: [GRG] NewAbs: Mouse Skin Rejuvenation with NF-kappa-B
Date: Saturday 01 December 2007
From: "L. Stephen Coles, M.D., Ph.D." <scoles at grg.org>
To: "Gerontology Research Group" <grg at lists.ucla.edu>

Gentlemen: 

         I am really impressed with the high intellectual quality of 
this discussion engaged in by people from all over the world who would 
not normally have found each other, except for the wonders of the 
Internet.  Keep up the good work.  

         The discussion also reveals the  vast complexity of our chosen
 topic, in that it deals with such a broad array of issues and expertise 
 that it's sometimes hard to 'see the forest for the trees'. (Think: The 
tale of the 'Blind Men and the Elephant'.)

         The sources of aging-phenotypes and the senescence of 
 virtually all multicellular creatures are multiple and refined by
 genetic calibration to occur essentially simultaneously through the
 force of evolution at a species' maximum lifespan (Think: 
 The poem about the "One-Hoss Shay"). Here are 12 candidates:

 1. Excessive inflammatory processes (no complex multi-cellular 
 organism could afford to survive in an ocean of microorganisms 
 containing potentially pathological parasites without evolving some 
 sort of protection against them in the form of what we now call
 an Immune System, whose balance is so delicate that it might 
 cascade either into (1) deficiency (immunosenescence) (secondary 
 to thymic involution?) leading to 'geriatric pneumonia'; or into (2) 
 hyperactivity (including autoimmunity) at any moment;

 2. Failure of Developmental/Reproductive clocks in the brain. 
 (Exhaustion of the precious supply of eggs in the ovaries or
 sperm in the testicles; both by different mechanisms);

 3. Failure of the Neuro/Endocrine Pituitary Axis (hGH, ACTH: 
 Cortisol, LH/FSH: Estrogen/Testosterone; TSH: Thyroid);

 4. Failure of DNA-repair enzymes (not to mention double-stranded
 breaks in chromosomes). (HGS Progeria; Bloom's Syndrome);

 5. Failure of mitochondria to sustain a sufficient supply of ATP 
 over time without a flood of ROS from damaged/broken membranes
 near the electrically-charged Krebs Cycle and the Electron Transport
 Chain;

 6. Failure of Telomeres to relengthen in certain tissues/Telomerase;

 7. Trading-off with the failure to control cellular replication 
(Cancer);

 8. Failure of adult stem cells to maintain youthful tissue architecture
 (muscle, sensory nerves, etc.) without fibrosis, all over the body;

 9. Failure of the Cellular Chaperone System to fold proteins properly;

 10. Failure of the species-specific Longevity-Determining Genomic 
 Network to remain active (a catch-all category);

 11. Accumulation of undigestible junk within cells (Lipofuscin);

 12. Accumulation of undigestible junk outside cells, especially on
 vessel walls leading to progressive congestive heart failure (CHF)
 and/or strokes (atherosclerotic plaques in arteries or amyloid 
 formation on veins or in the brains of Alzheimer's patients).

         Did I leave anything out?  Even if I did, I suspect that many 
 new forms of the 'Grim Reaper' will appear on the horizon once these
 issues are understood and resolved by appropriate engineering 
 interventions.

         The only reason for my optimism that we could resolve all these 
 daunting challenges in our lifetimes is that interventions do not 
always  require a full understanding of what's going on 'under the 
covers'.  For example, we don't need to understand the molecular 
mechanism of slow blindness from bilateral cataract formation in the 
lenses of the eye (normally-transparent proteins misfold, becoming 
opaque and causing cloudy vision leading to blindness), if a simple 
surgical replacement with clear plastic lenses by a skilled 
ophthalmologist is sufficient to regain 20/20 vision (except for 
distance accommodation).  This is one of the most common surgeries 
performed in the world.

         Through my cloudy crystal ball, I can distinguish three 
specific boundary conditions that permit some degree of optimism:

 1. Eggs 'know' how to reprogram DNA to full pluripotency in a zygote
 (Fact: No Homo Sapiens babies are born old [at least for the last 
200,000  years that we've been on this planet]). And we now know 
(roughly) how to perform this trick in adult human cells too.  BTW, 
this event occurred only in the last few months, and we still need to 
refine the methodology in cell culture (using chemokines rather than 
through the use of a viral vector to insert potentially tumorogenic 
genes) to amplify millions of histocompatible partially-differentiated 
stem cells that can be infused into organs of the body (~50 trillion 
cells) or repair of tissues having undergone cellular apoptosis and 
subsequent sclerosis.

 2. Comparative genomics of different species should reveal why 
different mammalian gene networks have such radically different 
longevity phenotypes (European Tree Shrews [< 1 year] vs. Bowhead 
Whales  [> 220 years])(with an ~1,000-fold difference). This subgoal 
can reasonably be expected to be accomplished jointly by molecular 
biologists at CalTech, Stanford, and MIT within the next five years.  A 
Drug Discovery Program to intervene in these networks might take 
another ten years.  This will take work, but, in my view, it is doable 
in our lifetimes, providing one can expect to live another 15 years.  
If you can't then all bets are off.

 3.  A new form of hGH Secretagogue has recently become available 
(Sermorelin). The GRG expects to conduct a clinical trial in 2008 for 
selected subjects who meet our admission criteria and have a diagnosis 
of adult-onset Growth Hormone  Deficiency Syndrome (based on low IGF-1 
laboratory values).  Dr. Karlis Ullis, M.D. of Santa Monica will serve 
as PI along with Dr. Richard Walker and myself as coinvestigators.  I 
am in the process of editing an Informed Consent now and will let 
anyone know more about this study if you E-mail me off-line.  BTW, this 
 intervention is expected to add a few more years to one's life 
expectation if it works as we believe it will, and virtually everyone 
suffers from this diagnosis once they pass 60 yo.  The results of the  
90-day trial will be published in a peer-reviewed journal at the end of 
2008.

 Best regards,

 Steve Coles 
 _______________________________________________
 GRG mailing list
 GRG at lists.ucla.edu
  http://lists.ucla.edu/cgi-bin/mailman/listinfo/grg
 
 L. Stephen Coles, M.D., Ph.D., Co-Founder
 Los Angeles Gerontology Research Group
 URL:  http://www.grg.org
 E-mail: scoles at grg.org
 E-mail: scoles at ucla.edu    
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