Anti-Aging Medicine: Supplemental Notes 4 and Links

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Highlight Links
[82s] Hyperlinked Notes, Synopsis, and Review of Molecular Gerontology, ed. Suresh Rattan and Oliver Toussaint.
[83s] Notes on Drug Bioavailability, ed. Van de Waterbeemd.

[82s] Hyperlinked Notes, Synopsis, and Review of
Molecular Gerontology, ed. Suresh I.S. Rattan & Olivier Toussaint, Plenum Press, 1996. [Links, Books, Papers, at Amazon.com, US National Lab, Danish Centre]
This 10-year-old book still contains many ways to phrase questions to Internet search engines for keeping up with the latest results in the field.

Chap.1: Genetics of Aging and Multifactorial Diseases, by Slagbloom & Knook.
Aging processes involve changes in
(1) hormone status. [Books, LifeExtension].
(2) response to mechanisms of stress. [Links, Papers, LifeExtension].
(3) structural components [Books, Papers, LifeExtension], including
____(a) the intracellular matrix. [Books, LifeExtension].
____(b) the extracellular matrix. [Books, LifeExtension].
____(c) chromatin. [Books, LifeExtension].
____(d) the primary DNA sequence. [Books, LifeExtension].
____(e) the protein synthesis machinery. [Books, LifeExtension].
____(f) other structural components. [Books, LifeExtension].
Maximum life span [LifeExtension] and the mortality rate doubling time (MRDT) appear to be species-specific [Books], indicating that these characteristics are determined by a specific genetic component [Books]. See species life spans [Links, Papers] and maximum human lifespan [Links, Books, Papers].

Major lines of research dominating experimental investigations of the genetics of aging [Books, Links, Papers, LifeExtension]:
(1) Candidate longevity genes. [Links, Books, Papers, LifeExtension].
(2) Accumulation of somatic defects. [Links, Books, Papers, LifeExtension].
(3) Genetic control of longevity via selection experiments. [Books, Links, LifeExtension].
(4) Genetic control of longevity via construction of transgenic animals. [Links, Books, LifeExtension].
____(a) Drosophila. [Links, Books, Papers, LifeExtension].
____(b) C. Elegans. [Links, Books, Papers, LifeExtension].
____(c) now include transgenic mice. [Books, Links, Papers, LifeExtension]

Somatic genetic loci of interest in diseases of aging: [Books, Links, Papers].
(1) DNA repair. [Books, LifeExtension, Cats Claw Extract]
(2) DNA proofreading. [Books, LifeExtension].
(3) Accuracy of protein synthesis. [Books, LifeExtension].
(4) Protein turnover. [Books, LifeExtension].
(5) Oxygen radical scavenging. [Books, LifeExtension].
(6) Acute phase response. [Books].

Molecular age-changes in Somatic Cells: [Links, Books, LifeExtension].
(1) DNA. [Links, Books, LifeExtension].
____(a) chromosomal aberrations. [Links, Books, LifeExtension] [Avoid with curcumin and carnosine].
____(b) chromatin structure. [Links, Books, LifeExtension].
____(c) DNA sequence mutations. [Links, Books, LifeExtension].
____(d) DNA methylation changes. [Links, Books, LifeExtension].
____(e) DNA/protein interactions. [Links, Books, LifeExtension].
____(f) telomere length. [81s] [Links, Books, LifeExtension] Average white blood cell & colon mucosa telomere loss is 33 bp/year in vivo in men, and, in external cell cultures, about 50 bp per population doubling in vitro. Between the ages of 4 and 95 telomere restriction fragment lengths decrease in the range from 10,000 to 5,000 bp. Compensating telomerase activity is only noticible in germ cells. Immortalized cells in culture show telomerase activity. Telomere length reduction in blood lymphocytes may be strongly influenced by individual genetic polymorphisms. Telomere loss in vivo was more prominent in tissues associated with atherosclerosis such as iliac arteries than in tissues free of atherosclerosis, even in the elderly. Exhaustion of endothelial cells from iliac arteries via replicative senescence may be involved in atherosclerotic plaque formation.
____(g) X-inactivation maintenance. [Links, Papers]
____(h) ss, ds breaks; [Papers, Links].
____(i) ss, ds adducts [Links, Papers, LifeExtension].
(2) RNA. [Links, Books, LifeExtension]
____(a) constitutive transcription levels. [Links, Papers, LifeExtension].
____(b) induction and extinction of transcription. [Links, Papers].
____(c) hnRNA processing. [Links, Books, Papers].
____(d) stability of mRNA. [Papers, Links, Books, LifeExtension].
(3) Protein. [Links, Books, Papers].
____(a) histones. [Links, Books, Papers, LifeExtension]
____(b) extracellular matrix proteins. [Links, Books, Papers, LifeExtension].
____(c) cytoskeleton proteins. [Papers, Links, Books, LifeExtension].
____(d) stress proteins. [Papers, Links, Books, LifeExtension].
____(e) receptors. [Links, Books, Papers, LifeExtension].

Reversible intermediates of
(1) oxidation of lipids by free radicals [Links, Books, Papers].
(2) oxidation of DNA by free radicals [Links, Books, Papers, LifeExtension].
(3) glycation of DNA [Links, Books, Papers].
(4) glycation of collagen [Links, Books, Papers].

Irreversible products of
(1) oxidation of lipids by free radicals [Links, Books, Papers, LifeExtension].
(2) oxidation of DNA by free radicals [Links, Books, Papers, LifeExtension].
(3) glycation of DNA [Links, Books, Papers, LifeExtension].
(4) glycation of collagen [Links, Books, Papers, LifeExtension].

Irreversible products of reactions include
(1) lipid peroxides [LifeExtension].
(2) collagen crosslinks [LifeExtension].
(3) DNA crosslinks [LifeExtension].
(4) DNA mutations. [LifeExtension].

Accumulation of mitochondrial DNA mutations in human brain. [Links, Books, Papers].
Tissue areas that accumulate metals may accumulate glycated protein. For instance, see zinc accumulation in the hypothalamus.
Chap.2. Ageing and Cancer A Struggle of Tendencies
by Anastassia Derventzi, E.S.Gonos, and Suresh I.S. Rattan.
Homeostatic balance at the cellular level - [Books, Links].

Phenotype of the Senescent Cell in Vitro [Books, Links, Images]
(See also Phenotype of the Senescent Cell [Books] in Vivo [Books]).

Physiology [Books, Links, Papers].
(1) Reduced response to growth factors and other mitogens. [Books].
(2) Increased sensitivity to toxins and drugs. [Links]
(3) Altered Calcium flux. [Links].
(4) Altered pH. [Books]
(5) Altered viscosity. [Books, Links].
(6) Altered membrane characteristics. [Books].
(7) Altered differential regulation of signal transduction pathways. [Links]

Morphology
(1) Large size.
(2) Loss of fingerprint-like arrangement in parallel arrays.
(3) Irregular shape.
(4) Increased granularity.
(5) Increased number of vacuoles.
(6) Increased number of dense lysosomal granules with high autofluorescence.
(7) Multinulceation and heteroploidy.
(8) Highly polymerized cytoskeletal actin filaments.
(9) Disorganized microtubules.

Cell Cycle Characteristics
(1) Cessation of DNA synthesis.
(2) Cells arrested in G1 unable to pass restriction point.
(3) Over-expression of tumor suppressor genes.
(4) Accumulation of inactive complexes of some cyclins.
(5) Reduced levels of cyclin-dependent kinases (cdk)
(6) High levels of cdk-inhibitors.

Biochemical and molecular characteristics
(1) Reduced activity, specificity and fidelity of various enzymes.
(2) Accumulation of altered and abnormal proteins.
(3) Reduced rates of DNA and protein synthesis.
(4) Altered profile of transcription factors.
(5) Increased DNA damage.
(6) Altered pattern of post-translational modifications.
(7) Reduced rate of protein degradation.
(8) Altered expression of several genes.
(9) Loss of cytosine methylation in DNA.
(10) Reduced length of telomeres. [81s]

[83s] Notes on Drug Bioavailability, edited by H. van de Waterbeemd.
Drug bioavailability [Index, Links, Wikipedia, Books] of orally taken compounds is worst when the molecular weight is > 500, the calculated octanol/water partion is > 5, the number of H-bond donors is > 5, and the number of H-bond acceptors is > 10. (Hence, we concentrate on small-molecule telomerase activators, and for the conjugate part of a telomere remodeling cycle, on small-molecule sirtuin activators with a molecular weight < 500 such as resveratrol and quercetin, when small-molecule telomerase inhibitors like silymarin, garlic, and curcumin may also be taken.)
Cells used for experiments:
American Type Culture Collection - ATCC
European Collection of Cell Cultures - ECACC
Caco-2 cells for modeling intestinal absorption, also MDCK cells.
Note that sodium butyrate is often used to induce cellular differentiation. Without the appropriate microenvironment, many cells return to a relatively undifferentiated type of adult stem cell.
Paracellular vs. Transcellular Transport
[Books/Paracellular Transport, Books/Transcellular Drug Transport].
EDTA enhances the transport of paracellularly transported compounds [Books], but not of transcellularly transported compounds [Books]. p. 112.
"Molecules with a large molecular weight are confined to the transcellular route...". p.113. See also the transcytotic transport pathway [Books] and carrier-mediated transporters [Books].
Absorption from the Human GI Tract
Bioavailability can be improved by solvents that improve drug solubility.
"Bioavailability of drugs following oral administration is influenced by solubility and dissolution, transit time, GI stability, intestinal permeability, and first-pass extraction in the gut and the liver. p. 156.
Drugs may be transported by passive diffusion or by various carrier-mediated transporters. There are various intestinal transport proteins and enzymes. [Books/drug transporters]
Most nutrients are absorbed in the proximal jejunum [images]. Many carrier proteins, channels, and enzymes are expressed in this highly absorptive part of the GI tract. Absorbed drugs may have an affinity to an intestinal transport protein. p.169. If the drug is highly polar, it is unlikely to be absorbed by passive diffusion. Protein transporters include oligopeptide carriers and the amino acid transport family. These are expressed in the small intestine.
Topical (Transdermal) Drug Bioavailability [Books].

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Be sure to check a PDR (Physician's Desktop Reference) regarding dosage, contraindications, and side effects. See also Wal-Mart's checker for Drugs and Drug Interactions and Google Books Pharmaceutical References. It is best to use quality pharmaceuticals from reputable manufacturers according to the instructions of the manufacturer, and to avoid using mere chemicals that may be under investigation for pharmaceutical applications. Many of the tips and clues in this document could benefit from further testing and research.

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