Slowing the Clock: Understanding the Biochemistry of Aging and Age-Related Diseases
Introduction
Aging, a multifaceted and intricate process, involves the gradual decline of cellular functions. It stands as a primary risk factor for various human pathologies, including cancer, cardiovascular diseases, and neurodegenerative disorders. While the rate of aging is influenced by both genetic and biochemical processes conserved throughout evolution, visible signs of aging typically emerge after maturity.
Facets Of Aging
Aging encompasses two key aspects:
- Length of time: Chronological age.
- Senescence: The biological process of aging at the cellular and organismal level.
Both aging and senescence are shaped by a complex interplay of genetic and environmental factors.
Genetic Basis
The lifespan of a species appears to be intrinsically linked to genes that govern the balance between early growth, reproduction, and somatic maintenance. Molecular evidence suggests that certain genetic components of longevity are shared across different species. Two primary gene sets play a crucial role in aging and its prevention:
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Genes encoding DNA repair enzymes: Species with more efficient DNA repair enzymes tend to live longer. Mutations in these enzymes have been implicated in premature aging syndromes like progeria in humans.
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Genes encoding proteins involved in the insulin signal pathway: Extending lifespan in various species has been linked to the suppression of insulin and insulin-like growth factor signaling. This suppression leads to:
- Reduced mitochondrial electron transport and increased sensitivity to reactive oxygen species (ROS).
- Increased production of enzymes that combat oxidative damage and contribute to DNA repair.
- Enhanced fertility.
A key player in this genetic orchestra is the p53 protein, often dubbed the "guardian of the genome." This protein regulates cell division and can:
- Halt the cell cycle, leading to cellular senescence in rapidly dividing cells.
- Trigger apoptosis (programmed cell death) through Bax genes.
- Activate DNA repair enzymes.
P53 activation can be triggered by factors like UV radiation, oxidative stress, and DNA damage. Interestingly, the absence of lamina A, a protein linked to Hutchinson-Gilford progeria, can also activate p53, suggesting a potential mechanism for this premature aging syndrome.
Environmental And Epigenetic Basis
Beyond genetics, environmental and epigenetic factors significantly influence aging. These factors include:
- Oxidative stress: Leading to protein and DNA damage.
- Non-infectious chronic inflammation: Contributing to cellular and tissue damage.
- Alterations in fatty acid metabolism: Affecting energy production and cellular function.
- Accumulation of end products of metabolism: Interfering with cellular processes.
- Alterations in neuroendocrine systems: Disrupting hormonal balance.
- Loss of post-mitotic cells: Such as neurons and muscle cells, leading to functional decline.
Aging Theories
Numerous theories attempt to unravel the complexities of aging. One prominent theory centers around the role of oxidative stress:
- Metabolic-driven oxidative stress: Increased and unopposed metabolic activity leads to elevated ROS levels, contributing to various age-related diseases.
- Mitochondrial dysfunction: Mitochondria, the powerhouses of cells, are major sources of ROS. Damage to mitochondrial DNA (mtDNA) from ROS can lead to:
- Increased ROS production.
- Proton leakage.
- Decreased ATP production.
- Free radical damage: ROS can damage cellular components like enzymes, nucleic acids, and lipids, both within and outside mitochondria. This damage contributes to inflammation, a key driver of age-related pathologies such as cancer, cardiovascular diseases, arthritis, and neurodegenerative diseases.
- Mitochondrial decline: Aging is associated with a decrease in the number and efficiency of mitochondria, leading to reduced energy production and increased superoxide generation.
Other theories of aging propose various mechanisms:
- Telomere shortening: Shortened telomeres, protective caps on chromosomes, can trigger cellular senescence. However, this theory doesn’t fully explain aging in non-dividing cells like neurons.
- Hormonal imbalance: Dysregulation of reproductive hormones, initially promoting growth and development, may contribute to senescence later in life.
- Damage accumulation: Aging could be a result of accumulated damage and waste products that overwhelm cellular repair mechanisms.
- Programmed aging: The existence of a biological "time-switch" that controls development and triggers self-destruction.
- Autoimmune theory: Increased antibodies attacking the body’s own tissues contribute to aging.
- Hormesis effects: Beneficial effects arising from the body’s response to low-intensity stressors.
- Life history theory: Aging as a trade-off between early life investment in growth and reproduction versus later-life maintenance and repair.
Promoting Longevity
Several interacting agents may promote longevity. They include:
- Calorie restriction
- Protection against oxidative stress
- Factors activated by a suppressed insulin pathway
Biochemistry Of Hiv/Aids
The viral RNA is acted upon by the retrovirus after entry into the cells.
- A DNA strand with complementary sequence is produced.
- Then RNA strand is hydrolysed by RNase-H.
- Keeping the DNA minus strand as the template, a complementary (plus strand) of DNA is synthesized.
- The DNA double strand (proviral DNA) migrates into the nucleus of the host cell.
- The viral DNA is then integrated into the host cell DNA by the action of the viral integrase.
Retroviruses do not replicate in non-dividing cells. Similarly HIV also requires activation and division of T cells for the viral particle synthesis.
- The viral genes are transcribed and translated by the host cell mechanisms.
- The products of gag and pol genes, proteins p55 and p160.
- The precursor big proteins are incorporated into the virus assembly.
- This is then cleaved by host cell proteases into gp120 and gp41.
- These are then inserted to host cell membrane.
- Then the virions are evaginated out.
- During this process, part of the host membrane, along with gp120 and gp41 are added.
The infected host cell lives only for a day and half.
Biochemistry Of Cancer
- Free radicals produce DNA damage.
- Accumulated damages lead to somatic mutations and malignancy.
- Cancer is treated by radiotherapy.
- Irradiation produces reactive oxygen species in the cells which trigger the cell death.
