Pathophysiology of aging, death of the organism
Aging of the organism[edit | edit source]
Aging is defined as a decline in vitality with age and an increased susceptibility to various diseases. It is a universal process that appears similar in all organisms, although it proceeds at different rates. From a molecular perspective, it represents the inability to maintain the proper structure of biomolecules indefinitely = a “systemic molecular disorder” (Hayflick). It is important to distinguish between two basic terms:
- average lifespan – a statistical quantity; all members of a population at a given place and time (e.g., year 2000 – men 71 years, women 78 years);
- maximum lifespan – derived from how long the longest-living individuals survive; how long it is possible to live under optimal conditions (115–120 years); it does not change.
Pathogenesis of aging[edit | edit source]
There are many theories concerning the process of aging. In general, it is accepted that with increasing age, errors accumulate in the organism that it is no longer able to sufficiently repair. The most significant influences are mitochondrial changes and the effects of free radicals.
Free radical / mitochondrial theory of aging[edit | edit source]
As early as 1956, the theory of accumulation of oxidative damage with age was proposed. Later, the mitochondrial theory was formulated, stating that mitochondria are the main source of oxygen radicals in the organism.
Mitochondrial DNA mutates about 10 times faster than nuclear DNA. This is because mtDNA is not protected by histones and has a less effective repair system. The production of radicals in mitochondria leads to the accumulation of mutations in mtDNA.
As a result, dysfunction of respiratory chain complexes occurs → increased radical production ⇒ heart failure, muscle weakness, diabetes mellitus, dementia, and neurodegeneration.
Slightly damaged mitochondria produce less energy than the cell requires.
Life-time Energy Potential[edit | edit source]
This is considered evidence supporting the mitochondrial theory. In most mammals, lifespan is determined by a certain total number of heartbeats / oxygen consumption. Smaller mammals have a more intensive metabolism and faster heart rate, and therefore live shorter lives.
Theory of accumulation of defective components in the cell[edit | edit source]
Another theory of aging processes is associated with catabolic failure of the organism. Defective components accumulate in the cell. Under normal conditions, substances are degraded in several ways:
- proteins with a short half-life: proteasomes;
- proteins with a long half-life and organelles: autophagy (macroautophagy – whole organelles; microautophagy – macromolecules, small organelles; chaperone-mediated autophagy);
- mitochondria: lysosomes.
If degradation in lysosomes is incomplete, iron is released from mitochondria. Free oxygen radicals are formed, along with lipid peroxidation, aggregation, and polymerization of oxidized proteins and lipids. Lipofuscin (known as the “aging pigment”) is formed, as well as defective mitochondria and protein aggregates. These can initiate apoptosis.
The only way to eliminate waste substances is through cell division. The waste is not removed, but rather distributed into daughter cells, which reduces its concentration. This becomes a problem in cells that live very long and divide poorly, such as cardiomyocytes and hepatocytes.
Physiology of aging[edit | edit source]
During aging, various systems of the human body are affected. Changes occur in the nervous system (myelination of axons, number of synapses), the musculoskeletal system, and the blood vessels and lungs are also affected. In people older than 65 years, heart disease is one of the most common problems.
Basic concepts[edit | edit source]
Hayflick limit
The maximum number of divisions that a cell undergoes before it dies varies among different cell types. It applies to all somatic cells, but not to cancer cells. In cells of older individuals, the number of possible divisions is lower.
Example: fibroblasts and epithelial cells never reach the Hayflick limit (they divide a maximum of about 50–70 times—humans do not live long enough for that many cell divisions to occur).
Telomerase
A ribonucleoprotein with its own RNA primer that extends the ends of chromosomes during DNA replication. Most cells in the human body do not require telomerase (they divide little or not at all). Stem cells, germ cells, and activated immune cells do contain telomerase. Telomerase is associated with carcinogenesis.
Example: mouse somatic cells have active telomerase, unlike human cells. Experimental knock-out of the mouse gene for telomerase led to premature aging.
How to slow down aging?[edit | edit source]
Antioxidants They suppress the formation of free radicals, which are a cause of disease 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 center of thioredoxin reductase and glutathione peroxidase—enzymes involved in antioxidant defense).
However, antioxidant dietary supplements can also be harmful (β-carotene belongs among teratogens, vitamins E and A may increase mortality). Vitamin C and selenium show no effect. Administration only makes sense if the metabolism itself is defective.
Why they sometimes do not help:
- At higher doses, they have no effect.
- They act where they should not: inhibition of stress responses, interference with defense against infections, tumor cells, and appropriate apoptosis.
- They have effects other than antioxidant ones: tocopherols are anti-inflammatory, β-carotene can act as a co-carcinogen (especially with smoking or environmental toxins).
Caloric restriction
Reduction of food intake while maintaining biological quality. It prolongs maximum lifespan, reduces oxidative stress and tumor incidence, and slows aging. An organism surviving unfavorable conditions (reduced food intake) allocates more energy to maintenance (and less to reproduction).
Example: It also works in warm-blooded organisms (e.g., mice) with constant metabolic intensity (reducing intake to one quarter can extend lifespan up to twofold).
Mechanism:
- suppression of IGF-I (somatomedin C) and insulin signaling;
- sirtuins – histone deacetylases, p53, etc.; inhibited by NADH, activated by NAD+.
Moderate physical activity
The need for energy stimulates the biogenesis and renewal of muscle mitochondria. A moderate level of stress (exercise) increases resistance to further stress → mechanism: induction of expression of heat shock proteins (chaperones) – a stress response.
Example: production of ROS (reactive oxygen species) in muscle tissue during physical activity – beneficial (the body needs to renew mitochondria, replacing the damaged ones).
Diet
A diet rich in fruits and vegetables is associated with a lower risk of cardiovascular diseases, diabetes mellitus, and some types of cancer (lungs, mouth/throat) – although the exact reason is unknown (optimal intake: 5 × 80 g per day).
Genetic Causes of the Aging and Death Process[edit | edit source]
The processes of aging are studied by the field of gerontology. Understanding the changes that accompany aging is important for adequate medical and preventive care for the elderly. Aging processes are individual.
Causes of Aging[edit | edit source]
- Biological studies of aging focus on the phenotypic manifestations of cellular aging:
- Free radical theory – these reactive metabolites interact with macromolecules of membranes, cellular structures, and nucleic acids, gradually negatively affecting their function;
- Genetic causes of aging – sought in the accumulation of somatic mutations:
- The functional consequences of gene and chromosomal mutations depend on their location, frequency, and the type of affected cells; even non-lethal mutations disrupt the synthesis of proteins important for metabolism and cell repair;
- Mutations can reduce the adaptive capacity of the cell and eventually lead to its death.
Telomeres[edit | edit source]
More detailed information can be found on the page Telomeres.
Molecular genetic findings show that age is programmed by the length of telomeres. Chromosomal telomeres consist of a large number of short repeats that are species-specific. In humans, the repetitive sequence of telomeres is TTAGGG, and their length is approximately 5–15 kb.
The telomere ends with a single-stranded segment; telomeric bases are methylated, which allows the formation of a specific loop structure in which methylated guanosines pair.
The structure of the telomere prevents DNA cleavage by deoxyribonucleases, fusion of DNA molecules within the genome, and enables DNA replication without loss of terminal sequences.
Elongation of telomeres is carried out by the complex enzyme telomerase (an RNA-dependent DNA polymerase). This enzyme is active only in:
- germline cells,
- stem cells of the bone marrow,
- stimulated T and B lymphocytes,
- and transformed (cancer) cells.
In differentiated somatic cells, telomerase is not expressed, and telomeres shorten with each cell division by approximately 100 base pairs.
Shortening of telomeres below 2.5 kb is critical for the cell—it stops dividing and apoptosis may be triggered. Cells with longer telomeres are capable of more divisions than cells with shorter telomeres.
Manifestations of Aging[edit | edit source]
Aging manifests as a decline in the function of individual organ systems. Basal metabolism decreases, as do pulmonary ventilation and blood flow through organs. The overall performance of the organism is reduced, as well as its ability to maintain internal homeostasis.
The efficiency of the immune system is also crucial for lifespan—it protects the organism not only from infections but also from neoplasms.
Factors that significantly influence lifespan include the quality of the environment and lifestyle.
