Oxygen

1. Oxygen: The paradoxical molecule that sustains and ages us

Oxygen is hailed as the Elixir of Life — a wonder tonic, a cure for ageing, a beauty treatment and a potent medical therapy. It is also purported to be a fire hazard and a dangerous poison that will kill us in the end.

Life-giving and life-taking. Oxygen is essential for life, enabling complex organisms to extract energy from food through cellular respiration. However, it's also a reactive molecule that can damage cells over time. This paradox is at the heart of understanding aging and longevity.

Evolutionary adaptation. Life on Earth has evolved numerous mechanisms to harness oxygen's power while mitigating its dangers. These include:

• Antioxidant enzymes like superoxide dismutase and catalase
• Cellular compartmentalization (e.g., mitochondria)
• DNA repair mechanisms

Historical perspective. The discovery of oxygen and its role in life processes was a pivotal moment in scientific history, involving scientists like Joseph Priestley, Antoine Lavoisier, and others. Understanding oxygen's dual nature has been crucial in fields ranging from medicine to space exploration.

2. Free radicals: The double-edged sword of cellular metabolism

If we know that free radicals are produced, or that they cause damage proportional to their rate of production. The problem with the free-radical theory, from the very beginning, was that correlations say nothing about causality.

Inevitable byproducts. Free radicals are produced as a natural consequence of cellular metabolism, particularly in the mitochondria. While they can cause damage to DNA, proteins, and lipids, they also play important roles in cell signaling and immune responses.

The rate of living theory. This theory suggests that organisms with higher metabolic rates age faster due to increased free radical production. However, exceptions like birds and bats challenge this simplistic view.

Oxidative stress and aging. The balance between free radical production and antioxidant defenses is crucial:

• Excessive free radicals lead to oxidative stress
• Chronic oxidative stress is associated with aging and age-related diseases
• However, some level of oxidative stress may be beneficial, triggering adaptive responses

3. Antioxidants: Nature's defense against oxidative stress

There is still no evidence that antioxidant supplements increase maximum lifespan. Instead, a balanced diet probably corrects for vitamin deficiencies that might otherwise cut short our lives.

Complex network. Antioxidants are not just dietary supplements but a sophisticated system of molecules and enzymes that work together to neutralize free radicals and repair oxidative damage.

Dietary vs. endogenous antioxidants. While fruits and vegetables provide important antioxidants, the body also produces its own, such as:

• Glutathione
• Coenzyme Q10
• Lipoic acid

The antioxidant paradox. Excessive antioxidant supplementation may be harmful:

• It can interfere with beneficial oxidative stress responses
• May suppress important cellular signaling pathways
• Could potentially increase cancer risk in some cases

4. Mitochondria: The powerhouses and timekeepers of cells

The critical point is that the survival of bacterial life involves death on a massive scale. In 24 hours, a single bacterium can produce 248, or 1016, cells, with a total biomass of about 30 kilograms. Clearly, such exponential growth cannot be sustained.

Evolutionary origin. Mitochondria were once free-living bacteria that formed a symbiotic relationship with early eukaryotic cells. This endosymbiosis event was crucial for the evolution of complex life.

Energy and aging. Mitochondria are central to cellular energy production and aging:

• They generate most of the cell's ATP through oxidative phosphorylation
• They are a major source of free radicals
• Mitochondrial DNA is particularly vulnerable to oxidative damage

Mitochondrial theory of aging. This theory proposes that accumulated damage to mitochondrial DNA and proteins leads to cellular dysfunction and aging. However, the relationship is complex and not fully understood.

5. Evolution of longevity: Balancing reproduction and survival

If senescence is not necessary to life as such, and has not always been with us, then presumably it has evolved. If senescence evolved, then it must be determined at least partly by genes, as only traits that are genetically determined can evolve and be passed on to the next generation.

Trade-offs. Evolutionary theory suggests that longevity is balanced against reproductive success. Resources allocated to survival and repair come at the cost of reproduction and vice versa.

Selection pressure. The force of natural selection declines with age, as genes affecting late-life traits have less impact on reproductive success. This leads to the accumulation of deleterious mutations that act late in life.

Adaptive aging. In some species, programmed death may be advantageous:

• Clearing space for offspring
• Reducing competition for resources
• Maintaining genetic diversity in populations

6. Calorie restriction: A potential key to extending lifespan

Calorie restriction can increase the lifetime energy potential — we get more heartbeats. For male rats, this increase is in the order of 50 per cent.

Universal effect. Calorie restriction extends lifespan in a wide range of organisms, from yeast to primates, suggesting a conserved mechanism.

Metabolic adaptation. Calorie restriction triggers numerous physiological changes:

• Lowered metabolic rate
• Reduced inflammation
• Improved insulin sensitivity
• Enhanced stress resistance

Hormesis. The benefits of calorie restriction may be due to hormesis - a beneficial response to low-level stress that strengthens the organism's ability to cope with greater challenges.

7. The disposable soma theory: Why we age and die

The disposable soma theory argues that longevity is a trade-off between the resources committed to reproduction and those committed to bodily maintenance.

Resource allocation. This theory proposes that organisms allocate limited resources between maintaining the body (soma) and reproduction. The optimal balance depends on environmental factors and evolutionary history.

Evolutionary perspective. The theory explains why:

• Species with high mortality rates in the wild tend to age faster
• Long-lived species often have delayed sexual maturity and lower reproductive rates

Implications for human aging. Understanding this trade-off could lead to interventions that:

• Extend healthspan by improving somatic maintenance
• Potentially increase lifespan by shifting resource allocation

8. DNA damage and repair: The constant battle within our cells

We are left with the following conclusions. If senescence is not necessary to life as such, and has not always been with us, then presumably it has evolved.

Ongoing threat. DNA is constantly under attack from both endogenous (e.g., free radicals) and exogenous (e.g., UV radiation) sources. This damage, if left unrepaired, can lead to mutations, cellular dysfunction, and aging.

Repair mechanisms. Cells have evolved sophisticated DNA repair systems:

• Base excision repair
• Nucleotide excision repair
• Double-strand break repair
• Mismatch repair

Aging and repair. The efficiency of DNA repair mechanisms declines with age, contributing to genomic instability and age-related diseases. Enhancing these repair systems could potentially slow aging.

9. Telomeres and cellular senescence: Not the fountain of youth

In short, it seems fair to say that, for all the hullabaloo, telomerase does not hold the secret of eternal life.

Cellular clock. Telomeres, the protective caps at the ends of chromosomes, shorten with each cell division. This shortening serves as a cellular clock, limiting the number of times a cell can divide.

Replicative senescence. When telomeres become critically short, cells enter a state of senescence or programmed cell death. This mechanism helps prevent cancer but also contributes to aging.

Telomerase and immortality. While telomerase can extend telomeres and cellular lifespan:

• It's not a simple solution to aging
• Many cells in the body don't divide and aren't limited by telomere length
• Activating telomerase could increase cancer risk

10. Gender differences in aging: The role of hormones and metabolism

As Tom Kirkwood and Steven Austad have argued, the power of this effect is exemplified by the existence of the menopause.

Evolutionary perspective. The different reproductive strategies of males and females have led to differences in aging patterns:

• Females often live longer but experience a sharp decline in fertility (menopause)
• Males maintain fertility longer but often have shorter lifespans

Hormonal influences. Sex hormones play a crucial role in aging:

• Estrogen has protective effects on the cardiovascular system and bone density
• Testosterone influences muscle mass and bone density

Metabolic differences. Gender-specific metabolic traits affect aging:

• Females generally have lower metabolic rates and produce fewer free radicals
• Males often have higher muscle mass, influencing overall metabolism and aging

These differences highlight the complex interplay between genetics, hormones, and environment in the aging process, emphasizing the need for gender-specific approaches to longevity research and interventions.

Last updated: July 24, 2024