X-Message-Number: 27905
From: "Hare, Tim R" <>
Subject: Biochemical links to the the bane of A.G.E [was: RE: [CN]
Date: Wed, 3 May 2006 15:26:45 -0400

Related, a recent article in Mechanisms of Aging and Development
&md5=16e65cf5fe6f9443631bcbc949575ea6) reviews data supporting a link
between glycolytic intermediates, and benefits seen in caloric
restriction/dietary restriction (CR/DR).  

Given the recent spate of publications suggesting favorable comparison
between alternate day near-isocaloric fasting (ADNICF) and CR/DR, the above
is yet another potential biochemical explanation.

Perhaps data will ultimately show that much of what one gains (however
modest) from 40% AD-LIB CR, might be accessible through more *moderate
means*: net caloric intakes similar to the RDA 2000, but eaten in fewer
feedings, perhaps even intra-day.    

As well, given the body of literature on glycation intermediates and
advanced glycation end product impact on the proteome with attendant
proteome dysfunction (and CR/DR regulation of this), this is rather good to
see.  Pharmaceutical interventions in glycation, glycoxidation, etc, and
proteome integrity seem increasingly likely (Benfotiamine, being one of
particular interest, for me....very rich primary literature on this).

One can *even* speculate above ties to LAMIN-A (one of your other recent
finds), via integrity of the proteome, and increasing levels of aberrant
forms as a function of age.  Might interventions in the aging proteome per
the above, yield reductions in aberrant LAMIN-A.

Cheers, T-

Timothy R. Hare 
Automated Biotechnology (952) 
Bld NW-2, 503 Louise Lane, North Wales, PA 19454 
Merck E-mail: <mailto:> 
Voice: (267) 305-3235
Mobile (267) 984-7136
FAX: (267) 305-0182 

-----Original Message-----
From: CryoNet F [mailto:] On Behalf Of Doug Skrecky
Sent: Friday, April 28, 2006 1:32 PM
To: CryoNet F
Subject: [CN] presbyopia - the bane of age

[Although the human lens grows thicker with age, eye muscles also grow
stronger to compensate. The main cause of presbyopia appears to be due to
a large increase in lens stiffness driven by an age-associated
accumulation of glucosepane crosslinks. The first company to patent
eyedrops with glucosepane breakers, as a cure for presbyopia stands to
make billions. Young people may not realize this, but presbyopia is a
universal scourge in those over 50 years of age. The market for eyedrops
effective in treating presbyopia is very, very large.]

Ophthalmic Res. 2006 Jan 3;38(3):137-148 [Epub ahead of print]
Presbyopia: The First Stage of Nuclear Cataract?
  Presbyopia, the inability to accommodate, affects almost everyone at
middle age. Recently, it has been shown that there is a massive increase
in the stiffness(1) of the lens with age and, since the shape of the lens
must change during accommodation, this could provide an explanation for
presbyopia. In this review, we propose that presbyopia may be the
earliest observable symptom of age-related nuclear (ARN) cataract. ARN
cataract is a major cause of world blindness. The genesis of ARN cataract
can be traced to the onset of a barrier within the lens at middle
age. This barrier restricts the ability of small molecules, such as
antioxidants, to penetrate into the centre of the lens leaving the
proteins in this region susceptible to oxidation and post-translational
modification. Major protein oxidation and colouration are the hallmarks
of ARN cataract. We postulate that the onset of the barrier, and the
hardening of the nucleus, are intimately linked. Specifically, we propose
that progressive age-dependent hardening of the lens nucleus may be
responsible for both presbyopia and ARN cataract.

Prog Retin Eye Res. 2005 May;24(3):379-93. Epub 2004 Dec 19.
The mechanism of presbyopia.
  Accommodation in humans refers to the ability of the lens to change
shape in order to bring near objects into focus. Accommodative loss
begins during childhood, with symptomatic presbyopia, or presbyopia that
affects one's day to day activities, striking during midlife. While
symptomatic presbyopia has traditionally been treated with reading glasses
or contact lenses, a number of surgical interventions and devices are
being actively developed in an attempt to restore at least some level of
accommodation. This is occurring at a time when the underlying cause of
presbyopia remains unknown, and even the mechanism of accommodation is
occasionally debated. While Helmholtz' theory regarding the mechanism of
accommodation is generally accepted with regard to broad issues,
additional details continue to emerge. Age-related changes in anterior
segment structures associated with accommodation have been documented,
often through in vitro and/or rhesus monkey studies. A review of these
findings suggests that presbyopia develops very differently in humans
compared to non-human primates. Focusing on non-invasive in vivo human
imaging technologies, including Scheimpflug photography and
high-resolution magnetic resonance imaging (MRI), the data suggest that
the human uveal tract acts as a unit in response to age-related
increasing lens thickness and strongly implicates lifelong lens growth as
the causal factor in the development of presbyopia.

Mol Vis. 2004 Dec 16;10:956-63.
Massive increase in the stiffness of the human lens nucleus with age: the
basis for presbyopia?
  PURPOSE: To determine the stiffness of different regions of human
lenses as a function of age, and to correlate the biophysical
measurements in the lens center with nuclear water content. METHODS: A
custom made probe fitted to a dynamic mechanical analyzer was employed to
measure stiffness values at 1 mm increments across equatorial sections of
individual human lenses. Thermogravimetric analysis was used to determine
the percentage water content in the nuclei of human
lenses. RESULTS: There was a pronounced increase in lens stiffness over
the age range from 14 to 78. In the nucleus, stiffness values varied
almost 1,000 fold over this age range, with the largest change observed
in lenses between the ages of 20 to 60. Nuclear stiffness values
increased on average by a factor of 450. By contrast, in the cortex the
average increase in stiffness was approximately 20 fold over this
same time period. In lenses younger than age 30, the nucleus was found to
be softer than the cortex. This was true for all six lenses examined. In
contrast all lenses older than 30 were characterized by having nuclear
values higher than those of the cortex. In lenses over the age of 50, the
lens nucleus was typically an order of magnitude more rigid than that of
the cortex. The crossover age, when the cortical and nuclear stiffness
values were similar, was in the 30s. There was no significant change in
the water content of the human lens nucleus from age 13 to age
82. CONCLUSIONS: There is a marked increase in the stiffness of the human
lens with age. This is most pronounced in the nucleus. Since in vivo data
indicate that the nucleus must change shape significantly during
accommodation, it is highly likely that these measured changes in
physical properties will markedly diminish the ability of the lens to
accommodate, and thus may be a major contributing factor to
presbyopia. Since there was no measurable difference in the water
contents of the nuclear regions of the lenses, this marked increase in
stiffness is not due to compaction of the lens nucleus.

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