BIOCHEMISTRY OF AGING

 Aging – progressive and unfavorable loss of adaptation = ↑ vulnerability, ↓ viability and life expectancy
 ↑ life expectancy due to advances in health care and improvement of environment, ↓ infectious diseases, abolition of nutritional deficiencies
 ↑ number of elderly = ↑ demand for personal assistance

Mechanisms of Aging
BIOCHEMICAL  interference with the flow of cellular information from DNA to RNA to protein synthesis and degradation
CellMetab Random
Deterioration
 Molecules with one or more unpaired electron in its outer orbital, such as ROS (reactive oxygen species)
Free Radical  Normal by-products of essential reactions (ETC, respiratory burst, Fenton, Haber-Weiss), environmental sources (air pollution, smoke, radiation, toxic wastes)
Theory  Damage DNA and cause mutations, break cell membranes, destroys cellular identity, may lead to malignancies, cancer and death
 Oxidative stress can contribute to aging, counteracted by antioxidants (SOD, catalase, GSH peroxidase)
 Induced or spontaneous, change in nucleotide sequence, imbalance between genetic damage and repair systems
 DNA damage like single strand breaks, depurination, methylation, oxidation, depyrimidation, cytosine deamination, cross-linking
Somatic  Unrepaired mutations accumulate causing cellular deterioration and malfunctioning
Mutation and  Stability of DNA and efficiency of repair enzymes = longevity of species
DNA damage  Mitochondrial DNA more prone to oxidative damage, nearer to site of ROS production, lacks advanced repair mechanisms and histones
 ATP synthesis inhibited by activation of DNA-binding protein  polymers of ADP ribose using NAD  ↑ NAD inactivates ATP synthesis
 Diseases: Leber Hereditary Optic Neuropathy (NADH DH gene mutation), myoclonic epilepsy and ragged red fiber disease (tRNA gene mutation)
Error Crisis  Damage to protein synthesizing machinery, during transcription and translation
 Non-enzymatic attachment of sugars to proteins (glycation with glucose) = damage
Protein  Glycosylated proteins  Amadori products + oxidation  AGEs (advanced glycation end products)
Modification  AGEs increase rate of ROS production, accelerates atherosclerosis (binds with LDL), aggravates CHON cross-linking, affects pulmonary function
and Cross-  Galactose, fructose, deoxyglucose and ribose can cause glycation; glucose and fructose  sorbitol = retinopathy
Linking
 Racemization – less serious damage, D-isomer proteins, due to thermal energy
 Ubiquitination – attempt to degrade proteins, covers AGEs  Alzheimer’s plaques and tangles
Toxin and  Failure of cell to eliminate accumulated toxins and waste products (CytP450 ↓ with age)  interfere with efficient cell metabolism
Waste Product  Aluminum makes DNA inert, Lead is neurotoxic
Accumulation  Lipofuscin (age pigment) product of lysosomes, biomarker of aging, indicates oxidative damage
↑ Basal  Basal metabolic rate is inversely proportional to lifespan of species
Metabolism  ↑ BMR = ↑ generation of radicals and wastes
Genetic
 aging is genetically programmed or inherent
Programming
 Sequential switching on and off of certain genes
 Senescence – time when age-associated deficits are manifested
 Little different in lifespan in identical twins compared to fraternal twins
 Longevity genes: age-1, (Cu/Zn SOD, catalase), daf (insulin receptor gene), clk (growth, cell cycle time), mth and sod-1, Bcl-2 (anti-apoptosis)
 Apoptosis genes also present, as well as transcription factors that lack in aging cells
 Covalent modification of histones – affect life span, Plasma proteins – correlated with lifespan
 Heat shock proteins (HSPs) = ↓ in aging cells, ↑ in CRAN fed organisms
Programmed  Apoptosis – programmed cell death, due to lack of positive signals (GF, ILK-2) or presence of negative signals (oxidants, x-ray, UV, death activator signals)
Senescence
 3 Pathways:
o Internal – intrinsic, mitochondrial; mito Bcl-2  Bax  CytC  Apaf-1  activate Caspase 9  Caspase 3, 7  destruction of structural proteins, DNA degradation, phagocytosis
o External – death receptor pathway; external signals activate Fas and TNF receptors  activate Caspase 8
o Release of AIF (Apoptosis Inducing Factors) – mitochondrial membrane protein, release when signal is received; DNA destruction, uses no caspases
 Premature aging syndromes
o Werner’s – very high rate of telomere shortening, defective helicase
o Progeria – inverted insertion in Chr1q, telomeres at age 5 like an old person, may be due to faulty VitE metab
  CRAN (caloric restriction with adequate nutrition) extends lives of lab animals; slows down metabolism  longevity, ↓ FR
NUTRITIONAL  Caloric restriction due to hypothalamic pacemaker (via serotonin)
 ↓ caloric proteins and replacement of casein with soya bean protein = ↑ lifespan

Anti-Aging Nutritional Strategies

Caloric Restriction ↓ caloric intake = ↓ metab = ↓ O2 use = ↓ FR; do not forget balanced diet
Antioxidant Nutrients
VitA / Carotenoids FR scavenger, anti-singlet O2, chain breaking antioxidant (accepts e- from lipid peroxyradicals  FR intermediate), lycopene is most powerful (100x anti-singlet O2 than VitE)
VitC / Ascorbic Acid antioxidant, FR scavenger, aqueous environment, accepts single e- from ROS, uric acid protects VitC from oxidation, melatonin is anti-OH radical
tocopherols, α form is most potent, scavenges for ROS and FR, protects UFA, terminates FR propagation by being converted to tocopheryl quinone, stabilizes CoQ or helping electron
VitE
transfer to CoQ
GSH Gly+Cys+Glu – cysteine sulfhydryl (like in aCoA) is antioxidant, catalyzed by Se-GSH peroxidase
Antioxidant Minerals Zn, Mn and Se as cofactors for antioxidant enzymes; can react with NO2, can regenerate VitE from VitE radical
β-carotene = lung cancer Dietary fibers = colon cancer
VitC C = lung cancer, cataracts Fish oils = cardiovascular diseases, rheumatoid arthritis
Lycopene, Lipoic Acid = prostate cancer Tryptophan = sleep disturbance
Various Nutrients
Lutein = macular degeneration Phosphatidyl serine = neuronal degeneration
Selenium = cancer Arginine / Ornithine = GH synthesis
VitB6, folic acid, B12, PUFA= cardiovascular diseases