Aging organism

As aging we refer to a decrease in vitality with age and an increase in susceptibility to various diseases. It is a universal process that looks the same for all organisms, it just runs at different speeds. From a molecular point of view, it is an inability to restore the correct structure of biomolecules indefinitely = "systemic molecular disorder" (Hayflick).

It is important to distinguish two basic concepts:


 * average life expectancy = statistical quantity; all members of the population in place and time (eg: year 2000 - men 71 years; women 78 years);
 * maximum life expectancy = derived from how long people live the longest; how long it is possible to live under optimal conditions (115-120 years); it does not change.

Pathogenesis of Aging
There are many theories regarding the aging process. It is generally accepted that with increasing age, errors accumulate in an organism that is unable to correct them sufficiently. Mitochondrial and radical changes have the most significant effect.

Radical/Mitochondrial theory of aging
As early as 1956, the theory of the accumulation of oxidative damage with age was developed. Mitochondrial theory was later formulated: saying that mitochondria are a major source of oxygen radicals in the body. Mitochondrial DNA mutates 10 times faster than nuclear DNA. mtDNA is not coated with histones and has a less perfect repair system. The formation of radicals in the mitochondria leads to the accumulation of mutations in the mtDNA. As a result, disorders of the respiratory complexes occur → radical formation => heart failure, muscle weakness, DM , dementia , neurodegeneration. Slightly damaged mitochondria produce less energy than the cell needs.

Life-time Energy Potential
It is considered a proof of mitochondrial theory. In most mammals, life expectancy is determined by a certain amount of heartbeat / oxygen consumption. Smaller mammals have a more intense metabolism and faster heart rate, and therefore live shorter periods of time.

Theory of accumulation of defective components in a cell
The second theory of aging processes is associated with catabolic failure of the organism. Defective components accumulate in the cell. Under normal circumstances, substances are broken down in several ways:


 * 1) short half-life proteins: proteasomes ;
 * 2) long half-life proteins and organelles: autophagy (macroautophagy - whole organelles; microautophagy - macromolecules, small organelles; chaperone -mediated autophagy);
 * 3) mitochondrie: lysozome.

When incomplete degradation occurs in lysosomes, iron is released from mitochondria. Free oxygen radicals, lipoperoxidation, aggregation and polymerization of oxidized proteins and lipids are formed. Lipofuscin (referred to as aging pigment ) and defective mitochondria and protein aggregates are formed. They can initiate apoptosis.

The only way to get rid of waste is cell division. The waste is not removed, but only divided into daughter cells, thus reducing its concentration. The problem arises with cells that live a very long time and are less difficult to divide: cardiomyocytes, hepatocytes.

Physiology of Aging
As we age, various systems of the human body are affected. There are changes in the nervous system (axon myelination, number of synapses), musculoskeletal system, blood vessels and lungs are also affected. Heart disease is one of the most common problems in people over the age of 65.

Basic concepts
The maximum number of divisions that cells go through before their extinction varies from cell to cell type. It applies to all somatic cells, but not to cancer cells. The number of divisions is smaller in the cells of the elderly.
 * Hayflick limit

Example : fibroblasts and epithelial cells never reach the Hayflick limit (they divide a maximum of 50–70 times - one does not live long enough to have so many cell divisions). A ribonucleoprotein with its own RNA primer that complements the ends of chromosomes during DNA replication. Most cells in the human body do not need telomerase (they divide little or not at all). Stem, terminal and activated immune cells have telomerase. Telomerase is associated with carcinogenesis.
 * Telomerase

Example : Mouse somatic cells, unlike humans, have active telomerase. Experimental knock-out of the mouse telomerase gene led to premature aging.

Antioxidants
They suppress the formation of free radicals, which are the cause of the disease state and have significant effects on pathogenesis. These are reducing agents capable of stopping radical chain reactions.

Examples : vitamin E (tocopherol), vitamin C (ascorbate), β-carotene, selenium (present in the active site of thioredoxin reductase and glutathione peroxidase - enzymes involved in antioxidant protection).

However, antioxidant supplements can also be harmful (carotene is a teratogen, vitamins E and A increase mortality). Vitamin C and selenium have no effect. Administration makes sense if the metabolism itself is defective!

Why they sometimes don't help:


 * In higher doses, they do nothing.
 * It works where they do not have: inhibition of the stress response, prevents the fight against infection, tumor cells, justified apoptosis.
 * They also have non-antioxidant effects: tocopherols are anti-inflammatory, β-carotene is a co-carcinogen (with smoking or environmental toxins).

Calorie restriction
Limiting the amount of food while maintaining biological quality. It prolongs maximum life expectancy, reduces oxidative stress, the incidence of tumors and slows down aging. An organism surviving an unfavorable period (reduced food intake) devotes more energy to maintenance (less to reproduction).

Example : it also works with warm-blooded organisms (mouse) with a constant intensity of metabolism (we limit the amount to a quarter, it prolongs the life of mice up to twice)

Mechanism:


 * 1) suppression of IGF-I (somatomedin C) and insulin signaling ;
 * 2) sirtuins = deacetylases of histones, p53, etc .; inhibited NADH, activated NAD +.

Adequate physical activity
The need for energy stimulates the biogenesis and renewal of muscle mitochondria. Adequate dose of stress (movement) increases resistance to another → mechanism: induction of heat shock protein (chaperone) expression - stress response.

Example : ROS production in muscle tissue during physical activity - beneficial (the body needs to renew the mitochondria that replace the damaged ones).

Diet
A diet rich in fruits and vegetables is associated with a lower risk of cardiovascular disease, DM and some types of cancer (lungs, mouth / pharynx) - but we do not know why (optimally 5x 80 g per day).

related articles

 * Telomerase
 * Apoptosis
 * DNA replication
 * Premature aging syndromes
 * Antioxidants

Source
Lectures in genetics in the second year

Reference

 * 1) PLATENIK, Jan. Aging  [lecture on the subject Pathobiochemistry 3, General Medicine, 1st Faculty of Medicine, Charles University]. Prague. 12/1/2015 Also available from < https://ulbld.lf1.cuni.cz/prednasky-ke-stazeni >.