Author: BalanceGenics Anti-aging Research Team (How100.com)
In our modern society, where life expectancy is constantly increasing and living to 100 years is becoming more common, achieving healthy aging and avoiding the common decline in bodily functions and chronic diseases in the elderly is a dream for many.
However, despite numerous theories explaining aging—possibly numbering in the dozens to hundreds—none have provided a clear method or approach to combat aging, highlighting the complexity of the issue.
This report attempts to present a systematic explanation and approach to combating aging that has emerged in recent years: aging might be a process of biological individuals' epigenetic modifications gradually becoming disordered and collapsing, and induced pluripotent stem cell (iPSC) technology might reverse aging by erasing the epigenetic marks of aged cells.
The Nature of Aging
Aging and death are inevitable fates for almost all multicellular organisms, and humans are no exception. From an evolutionary biology perspective, aging is not a result of finely tuned biological mechanisms but rather a process where various biological mechanisms gradually fail and become unbalanced after the reproductive stage. If we were to make an analogy, aging is more like the gradual wear, cracking, and shattering of a fine glass vessel rather than a racing car speeding off a cliff.
Natural selection only acts on organisms before they complete reproduction. If a gene mutation only manifests its effects after reproduction, no matter how much it disrupts various precise biological regulatory mechanisms within the organism, it cannot be eliminated by natural selection. Therefore, over long-term evolution, harmful mutations that gradually manifest after reproductive age accumulate in the genomes of organisms, objectively leading to a decline in physiological functions and ultimately death.
This discussion not only theoretically explains the essence of aging but also provides important conceptual tools for humans to resist or even reverse aging. Based on this understanding, since aging is not the result of precise biological regulation, it is unlikely that there is a magical "aging switch" that, when flipped, could delay, halt, or even reverse comprehensive aging in humans. Instead, researchers need to carefully explore the biological processes that gradually fail and become unbalanced during aging, and then design methods to reactivate and realign these processes to achieve the effect of delaying or reversing aging.
However, the practical application of the above model faces many difficulties. Particularly, if one tries to understand the aging process from a single dimension and use that to combat aging, failure is almost predictable. Two famous examples are the shortening of telomeres and the increase in reactive oxygen species (ROS).
Telomeres are repetitive sequences at the ends of chromosomes that protect chromosome integrity but shorten with each cell division, affecting chromosome stability. Reactive oxygen species (ROS) are a series of chemicals, including oxygen ions and hydrogen peroxide, that easily react with surrounding substances due to their unpaired active electrons. In aging cells, mitochondrial dysfunction produces a large amount of ROS, damaging the structure and function of many cellular components. Shortened telomeres and elevated ROS levels are indeed observed in the aging of different species.
According to the logic just discussed, if ways to prevent telomere shortening or reduce ROS levels were found, it should be possible to delay or even reverse aging. However, in reality, researchers have not observed significant and consistent anti-aging effects. For example, although activating telomerase to extend telomeres in mice can delay aging, in humans, longer telomeres may correlate with a higher incidence of cancer. Additionally, a cross-species comparison shows that animals with longer telomeres may actually have shorter lifespans, and vice versa, as seen with mice and humans.
Moreover, overexpressing the protein SOD1, which eliminates ROS, does not delay aging in mice, and deleting the SOD gene, which eliminates ROS, surprisingly extends lifespan in nematodes.
The reasons behind these failures likely relate to the complexity of aging. Since aging is accompanied by many biological processes gradually failing and becoming unbalanced, it is difficult to say that altering a single process would produce noticeable anti-aging effects at the individual level, and it might even have counterproductive effects. For example, ROS are not only associated with aging but also serve as important biological signaling molecules within cells, so crude manipulation may be harmful rather than beneficial.
Epigenetic Biological Clock
Given the limitations of a single-dimensional approach, a more systematic perspective is needed to understand aging, such as the continuous changes in cellular genetic material, especially epigenetic changes.
Genetic information is carried by DNA, and changes in the DNA sequence fall under the realm of genetics. "Epigenetics" refers to changes in gene expression levels, biological processes within cells, and characteristics of the entire organism without altering the DNA sequence itself. For example, a fertilized egg divides continuously to produce the trillions of cells in the human body. These cells originate from the same fertilized egg and have almost identical DNA, yet they perform vastly different biological functions. Identical twins with the same genome can become increasingly different as they grow up. Similarly, an individual's physiological functions differ greatly between childhood and old age, even though the DNA sequence remains unchanged. These differences arise from factors beyond the DNA sequence, i.e., epigenetics.
Specifically, epigenetic changes include various types, such as chemical modifications of genomic DNA (particularly DNA methylation), which alter gene expression without changing the DNA sequence. Histone modifications, which influence chromosomal assembly, have similar effects. Other epigenetic mechanisms include RNA modifications, non-coding RNAs, post-translational protein modifications, and changes in the number and shape of organelles. Many believe that while the aging process does not change the DNA sequence of cells and organisms, it disrupts normal gene expression and protein function through epigenetic changes, causing many biological processes to become chaotic.
In 2011, researchers explored whether human aging is directly related to changes in epigenetic levels. They found that methylation at specific sites on the genome is age-related, and methylation at just three sites could accurately predict an individual's age. Further studies on the relationship between DNA methylation and age across the entire genome improved the accuracy of age prediction. This led to the concept of the "epigenetic clock," suggesting that continuous changes in DNA methylation reflect ongoing aging, not only in terms of increasing chronological age but also in declining health, the onset of chronic diseases, and rising mortality rates. In 2019, a small clinical study using the epigenetic clock attracted global media attention. Nine healthy participants received growth hormone injections to rejuvenate their aging immune systems. After a year, their epigenetic clocks indicated that, on average, they were 2.5 years "younger" than their peers.
A crucial question remains: how does the epigenetic clock measure aging? If we assume that the gradual loss of control over epigenetic modifications drives aging, what causes this loss of control?
In January 2023, a study by David Sinclair's lab at Harvard Medical School provided an important perspective. They suggested that random breaks in DNA molecules destabilize epigenetic modifications, leading to aging.
Specifically, researchers used transgenic techniques to express a nuclease from a fungus in mice, creating double-strand breaks (DSBs) at 20 specific sites on the mouse genome. These breaks could be quickly repaired without changing the DNA sequence but significantly altered the mice's epigenetic features, advancing their epigenetic clocks and accelerating various physiological aging indicators, such as weight loss, graying hair, reduced metabolism, hunched posture, decreased bone density, muscle mass, and cognitive function.
This study demonstrated that disrupting epigenetic modifications alone is sufficient to trigger rapid aging. Although the DNA breaks in this study were induced, many environmental factors, such as radiation and chemicals, can cause similar breaks.
This suggests a new understanding of aging: throughout an organism's development and reproduction, cellular DNA is continually attacked by internal and external threats, causing random DNA breaks. Most breaks are quickly and accurately repaired, but the process disrupts epigenetic modifications, leading to irreversible aging and death.
Reversing the Aging Clock
Is there a way to reverse the epigenetic clock of an organism and achieve anti-aging or even reversal?
One promising approach is stem cell technology, particularly induced pluripotent stem cell (iPSC) technology, which offers the possibility of rejuvenating aged cells and resetting the aging clock.
Stem cells have long been a hot topic, but fundamentally, they represent a cell's differentiation potential—the ability to generate various specialized descendants. Humans, as multicellular organisms, develop from a single fertilized egg through continuous division. This process involves "potential for function" changes, where the fertilized egg (a totipotent stem cell) can generate all types of cells in the body, but its descendants gradually lose this potential and specialize, becoming parts of the skin, nervous system, etc. This process is like a boulder rolling down a hill, with infinite path choices at the top, but fewer choices as it accelerates and eventually fulfills its biological mission at the bottom.
For a long time, this descent was considered an irreversible one-way street until 2006 when Japanese scientist Shinya Yamanaka published a paper in Cell, showing that by expressing four genes—Oct4, Sox2, Klf4, and c-Myc (OSKM or Yamanaka factors)—differentiated cells could be reverted to a pluripotent stem cell state. This groundbreaking discovery quickly revolutionized the field of life sciences, and soon, clinical trials began using this method to treat diseases. The principle is simple: instead of needing organ transplants, patients could have their cells reprogrammed to stem cells, then differentiated into the required organs for transplantation.
For instance, the NIH launched a 200-patient clinical trial in 2019 using this method to treat age-related macular degeneration. They took the patients' cells, reprogrammed them into pluripotent stem cells, then differentiated them into retinal pigment epithelial cells for transplantation into the patients' eyes. These reprogrammed cells, derived from the patients' own cells, were not recognized as foreign by the immune system, eliminating immune rejection.
After Yamanaka's discovery, researchers wondered whether it was possible to transform cells from old individuals back into stem cells and then use these stem cells to replace the old cells. This was challenging, especially in animals, as the reprogrammed cells often differentiated into tumor cells instead of normal tissues. However, in 2016, scientists found that expressing OSKM factors in mice not only prevented premature aging but also significantly delayed physiological aging. This success implied the possibility of reversing aging through epigenetic reprogramming.
Subsequent research showed that continuous expression of OSKM factors or other reprogramming genes could indeed turn various cells from old mice into induced pluripotent stem cells (iPSCs) and halt their biological clock. However, this also caused serious side effects like tumorigenesis.
In recent years, scientists have developed various methods to refine and optimize the effects of reprogramming genes, discovering that only a transient low-level expression of these factors is required. For instance, the Sinclair lab found that expressing three reprogramming factors (Oct4, Sox2, and Klf4) for three weeks could restore vision in aged mice without causing tumor formation or other serious side effects.
While there is still a long way to go before using this method for anti-aging treatments in humans, these findings provide a clear research direction and method to systematically combat aging.
Conclusion
In summary, this report presents a systematic explanation of aging and a possible approach to combat it:
- Aging is not the result of precise biological regulation but a process where biological mechanisms gradually fail and become unbalanced after the reproductive stage.
- The epigenetic clock, a measure of DNA methylation changes, reflects ongoing aging and offers a potential target for anti-aging interventions.
- Induced pluripotent stem cell (iPSC) technology, particularly transient expression of reprogramming factors, shows promise in reversing aging by resetting the epigenetic clock.
While further research is needed to refine these methods and ensure their safety and efficacy in humans, these findings offer hope for achieving healthy aging and potentially extending the human lifespan.
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