Is the accumulation of waste the root cause of aging? The mechanisms of aging

1. The 10-year gap between “average life expectancy” and “healthy life expectancy”

In modern Japan, average life expectancy for both men and women has exceeded 80 years, and thanks to scientific progress, some even say that an “era of 200-year life expectancy” may arrive in the future.

However, a major issue here is the discrepancy with “healthy life expectancy.” Healthy life expectancy refers to the period during which a person can live independently without requiring long-term care. Currently, there is a gap of about 10 years between average life expectancy and healthy life expectancy, and this period becomes an “unhealthy period.”

The goal of longevity research is to close this 10-year gap and live healthily until the very end.

2. The two major hypotheses of aging: Program theory vs. Wear-and-tear theory

In the scientific world, two major hypotheses have been debated regarding the cause of aging.

From research on “progeria” (Hutchinson-Gilford syndrome and Werner syndrome), where aging progresses rapidly due to genetic factors, it is a fact that specific genes are involved in cellular senescence.

However, studies on identical twins have revealed that for healthy individuals, the impact of genetics on life expectancy is about 20%, and the majority of the rest is determined by lifestyle and environmental factors. In other words, depending on our efforts, it is possible to slow down the rate of aging.

3. Cell “death” and “aging” are completely different

Our bodies are made up of approximately 37 trillion cells of 270 types. In understanding “aging,” the important point is that cell death and cellular senescence are completely different.

Cells die when they receive strong stress, but if they continue to receive moderate, weak stress that does not lead to death, the cells transform into “senescent cells.”

A major characteristic of senescent cells is that they fall into a state where they do not die, but can no longer divide or proliferate.

4. What is cellular senescence?

Cellular senescence refers to a state where cells have not died, but have lost their ability to divide due to some cause. There are broadly two types of cellular senescence.

• Replicative senescence: A phenomenon where cells reach their limit of division cycles and can no longer divide as they repeatedly divide.
• Induced senescence: A phenomenon where cells that originally have the ability to divide lose their ability to divide due to external or internal stress.

Main characteristics of cellular senescence

• Cessation of division: Cells can no longer proliferate.
• Morphological changes: While young cells are slim and small, when they age, the cells become large and flattened.
• Increased expression of aging-related genes: SASP (Senescence-Associated Secretory Phenotype) occurs, which highly expresses inflammatory cytokines and collagen-degrading enzymes.

Even when cells age, they do not disappear immediately. It is believed that the accumulation of senescent cells that have stopped dividing in the body is involved in the mechanisms of health and aging.

If there are fewer senescent cells, you are young, and if there are many senescent cells, you are old. It is a simple story, but it is a mechanism that has become clear in the past 10 years.

On the other hand, cellular senescence also has roles such as responding to emergencies when tissues are damaged and preventing abnormal cell proliferation. Therefore, senescent cells are not completely villains.

5. The fear of “chronic inflammation” caused by senescent cells

Senescent cells are not simply quiet cells whose functions have stopped. In fact, they behave like “zombie cells” that scatter harmful substances to their surroundings.

Senescent cells release inflammatory cytokines and collagen-degrading enzymes in large amounts due to a phenomenon called “SASP (Senescence-Associated Secretory Phenotype).”

As a result, even the surrounding normal cells receive stress and age or become cancerous, and the entire body falls into a state of chronic inflammation. This is believed to be one of the causes of various age-related diseases such as diabetes, kidney disease, and muscle weakness (sarcopenia).

6. What causes cells to age? 3 leading causes

There are various external and internal factors that cause cells to age. Here, we introduce 3 representative theories.

① Telomere theory (Division tickets)

“Telomeres” at the ends of chromosomes are called “tickets of life” because they shorten with each cell division.

However, recent research has shown that telomeres surprisingly remain in senescent cells, and that mice have longer telomeres than humans despite having shorter life expectancies, so telomeres alone cannot be said to be the root cause.

② Reactive oxygen species / Mitochondria theory

This is the theory that “reactive oxygen species” generated by mitochondria that produce energy damage DNA. Certainly, reactive oxygen species induce aging, but antioxidants alone cannot sufficiently explain aging, so this also cannot be said to be the sole main cause.

③ 【Most likely】 Waste accumulation (protein waste) theory

What the research team at Yokohama City University considers most likely is the accumulation of waste within cells, especially denatured proteins. Senescent cells have more protein waste accumulated than young cells.

In the research team's experiment, when they slightly suppressed protein synthesis and reduced the amount of waste, it was confirmed that cell life expectancy was extended.

7. The possibility of “rejuvenation (reverse aging)” proven by science

Once, it was a common sense in biology that “cells that have aged and enlarged once will never rejuvenate.”

However, when the aforementioned approach of “slightly suppressing protein synthesis and reducing waste” was tried, cells that had aged and spread flat once gradually became smaller and started proliferating again.

This phenomenon shows that the state of senescent cells is not necessarily irreversible, and by regulating the protein homeostasis in the cell, it may be possible to bring it closer to a young state.

8. Summary: Toward an era where aging can be controlled

Until now, it was thought that aged cells would not rejuvenate. However, in the laboratory, it is being proven that by adjusting the amount of protein, senescent cells can approach a young state.

Aging is not an “irresistible fate,” but is changing into something that can be “controlled” through lifestyle and the power of science.