Download Aging and Mitochondria - SENS Research Foundation

Glycation Crosslink Breakers:
Necessity and Prospects
John D. Furber
Legendary Pharmaceuticals
Gainesville, Florida
www.LegendaryPharma.com
© 2005 John D. Furber
Extracellular Aging
of Extracellular Matrix (ECM)
Glycation, Crosslinking, Stiffness
Cardiovascular hemodynamics, capillary circulation
Lens accommodation, cataracts, glaucoma
Arthritis
Bladder distensibility
Erectile dysfunction
Interactions of Cells and ECM:
Differentiation, Apoptosis
Inflammation
© 2005 John D. Furber
Alberts, et.al. Molecular Biology of the Cell. (4th Ed. New York: Garland Publishing, Inc. 2002.)
Elastin surrounds the Aorta
Alberts, et.al. Molecular Biology of the Cell. (4th Ed. New York: Garland Publishing, Inc. 2002.)
alpha-diketone Crosslink
•Forms from Glucose
•Perhaps Links Lysine to (Lysine or Cysteine or Histidine)
Ulrich P, Cerami A. Protein glycation, diabetes, and aging. Recent Prog Horm Res. 2001; 56:1-21.
Beneficial Crosslinks in Collagen
•Formed in young collagen
•Give strength to mature fibers
•Formed under enzymatic control
•Lysyl oxidase mediates Lys-Lys bond
•No sugar linker
Alberts, et.al. Molecular Biology of the Cell. (4th Ed. New York: Garland Publishing, Inc. 2002.)
Fibroblast Lineage
•Synthesize new Collagen and Elastin
•Arrange fibers properly in place
•Secrete enzymes to digest old ECM
Alberts, et.al. Molecular Biology of the Cell. (4th Ed. New York: Garland Publishing, Inc. 2002.)
Vicious Cycle Accelerates
ECM Crosslinking
• Crosslinked collagen has very small spaces.
• Restricts access to Fibroblasts and Enzymes
• Glycation crosslinking accumulates over time
• Collagen fibers drawn even more closely together
• Further slowing the natural turnover processes
© 2005 John D. Furber
Glucosepane Crosslink
•Forms from Glucose
•Links Lysine to Arginine
Sell DR, Biemel KM, Reihl O, Lederer MO, Strauch CM, Monnier VM. Glucosepane is a major protein
cross-link of the senescent human extracellular matrix. Relationship with diabetes. J Biol Chem. 2005
Apr 1;280(13):12310-5.
alpha-diketone Crosslink
•Forms from Glucose
•Perhaps Links Lysine to (Lysine or Cysteine or Histidine)
Ulrich P, Cerami A. Protein glycation, diabetes, and aging. Recent Prog Horm Res. 2001; 56:1-21.
K2P Crosslink
Lysinedihydropyridinium-
Lysine
Cheng R, Feng Q, Argirov OK, Ortwerth BJ.
Structure elucidation of a novel yellow
chromophore from human lens protein.
J Biol Chem. 2004 Oct 29;279(44):45441-9.
Two Nucleophilic Centers
Attack two Carbonyl Carbons
Crosslink Breaker
Alagebrium
Cl
CH3
ALT-711
O
N
+
S
CH 3
3-(2-phenyl-2-oxoethyl)-4,5-dimethyl thiazolium chloride
Drawing © John D. Furber 2005
Research We Need
• High-Throughput Screening (HTS) for
small-molecule breakers of glucosepane
and K2P.
© 2005 John D. Furber
Research We Need
• High-Throughput Screening (HTS) for
small-molecule breakers of glucosepane
and K2P.
• But... What if new small-molecule breakers
are not quickly found?
© 2005 John D. Furber
Research We Need
Plan B: Stimulate Natural Turnover
– Stimulate Fibroblasts or mesenchymallineage cells to do more of what they
already do.
– Extracorporeal
– In vivo injections
© 2005 John D. Furber
Research We Need
Plan C: Combination Breaker Therapy
– Develop or discover large enzyme
breakers for Glucosepane and K2P.
– Use them in combination with Alagebrium
© 2005 John D. Furber
Research We Need
Plan D: Nanobots to the Rescue!
– Design and build billions of little machines
to do what fibroblast and mesenchymal
lineage cells do, only better.
– Digest old collagen and synthesize new…
in exactly the right pattern.
© 2005 John D. Furber
In the Meantime…
Exercise, fasting, and low blood sugar levels
are good for your collagen.
[M Kjaer. "Metabolic activity and collagen turnover in
human tendon in response to physical activity.” J
Musculoskelet Neuronal Interact. 2005 Mar;5(1):41-52.]
© 2005 John D. Furber
Glycation Inhibitors in Food, Herbs,
and Supplements
• Vitamins B1, C, and E
•
•
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Curcumin
N-acetyl-cysteine
EGCG (black tea, green tea, white tea)
PABA
Quercetin
Resveratrol
Rutin
thyme
© 2005 John D. Furber
Extracellular Rejuvenation
is the answer to
Extracellular Aging
•
© 2005 John D. Furber
Parallel Development to
Maximize Early Success
1. HTS for small-molecule breakers of glucosepane
and K2P
2. Stimulate natural ECM turnover processes, such
as fibroblasts
3. Rational Design of enzymatic breakers of
glucosepane and K2P - Use in combination with
diketone breakers.
4. Nanobots (to be invented) come to the rescue
© 2005 John D. Furber
Legendary Pharmaceuticals
Scientific Advisory Board
• Ulf T. Brunk, MD, Ph.D.
• Alan R. Hipkiss, Ph.D.
• Judith Campisi, Ph.D.
• Shalesh Kaushal, Ph.D.
• Richard M. Cawthon, MD, Ph.D.
• Jiankang Liu, Ph.D.
• Ana Maria Cuervo, MD, Ph.D.
• Charles Ostman
• Aubrey D.N.J. de Grey, Ph.D.
• Kamala Rose, MD
• Ron Garren, MD
• Mark A. Smith, Ph.D.
• John C. Guerin
• Alexei Terman, MD, Ph.D.
• Kenneth Hensley, Ph.D.
• John H. Weiss, MD, Ph.D.
www.LegendaryPharma.com
© 2005 John D. Furber