The Telomerase Revolution

The Enzyme that Holds the Key to Human Ageing...and Will Soon Lead to Longer, Healthier Lives

Michael Fossel

• Editore: Atlantic Books
• Anno: 2015
• ISBN:
  9781782399117
• Argomento: Medicine
• Categoria: Medical Theory, Practice & Reference

Science is on the cusp of a revolutionary breakthrough. We now understand more about ageing - and how to prevent and reverse it - than ever before.

Twenty years ago, there was still considerable debate of the nature of human ageing, with a variety of competing theories in play. But scientific consensus is forming around the telomere theory of ageing. The essence of this theory is that human ageing is the result of cellular ageing. Every time a cell reproduces, its telomeres (the tips of the chromosomes) shorten. With every shortening of the telomeres, the cell's ability to repair its molecules decreases. It ages. Human ageing is the result of the ageing of the body's trillions of cells. But some of our cells don't age. Sex cells and stem cells can reproduce indefinitely, without ageing, because they create telomerase. Telomerase re-lengthens the telomeres, keeping these cells young.

In The Telomerase Revolution, Dr Michael Fossel, who has been at the forefront of ageing research for decades, provides startling insights into the nature of human ageing and describes how telomerase will soon be used as a powerful therapeutic tool, with the potential to dramatically extend life spans and even reverse ageing.

CHAPTER ONE

Theories of Aging

I don’t want to achieve immortality through my work. I want to achieve it through not dying.

—Woody Allen

A round 70,000 years ago, the first human beings—our direct ancestors—faced competition from Neanderthals and Homo erectus. These competitors were strong, intelligent, and fully capable of both language and tool-making. We were relatively slight and had little to recommend us as survivors as we moved into direct rivalry with earlier hominids. Our single major advantage was an odd one, an advantage that at first sight might seem to be a disadvantage. We were able to think and talk about things that don’t actually exist.

This made all the difference.

These were abstractions like tomorrow, god, art, science, dreams, and compassion. You can’t throw a spear at these things or eat them, steal them, break them, or destroy them. Yet these things not only made us human, but, oddly enough, made us far better survivors. Not only could we discuss intangible things that were necessary to social organization—like loyalty, cooperation, and strategy—but we could imagine things that that could be made—like weapons, tools, agriculture, and laws.

These abilities—abstract thought and imagination—are the foundation of our ability to create. Humans create not only art and tools, but also theories—religious and scientific explanations of how the world works—which ultimately allow us to change our own reality. Scientific advancement directly depends on this skill. We construct a vision of how reality works, we test our explanation, and then we use it to improve reality. A scientific theory is just that: a vision of reality that we can test and then use to improve our world. We cure disease, we grow food, and we gradually make human life easier and safer.

Man is the only creature that can do this. This ability to work with abstract concepts is lacking in other animals, even our closest relatives, chimpanzees and gorillas.

The key to using a theory to improve human life—or turning a dream into reality—is to have the right tools and the knowledge to use them. I often think of it as having a ship and a map.

OUTSMARTING A GORILLA

Koko was the first gorilla to use sign language. When she was three years old, I became her babysitter for six hours every week for a year. Koko understood more than a thousand signs and was adept at inventing games. She had learned to stop biting me (only after I bit her back) but would pull my laundry bag over her head and body—leaving nothing but two black, furry legs sticking out from the bottom of my gray cloth bag—then leap at me from the kitchen counter and try to chase me down. Her “rule” was that if she could catch me, she could bite me—but only as long as she kept the laundry bag over her head so I couldn’t see her biting. Somehow, a gray laundry bag made all the difference. It let her create a new way to play with me. On the other hand, while she was clearly smarter than any other animal I have ever met, she never mastered signs for the abstract concepts that are central to both human thinking and human society.

Sometimes the ship is simple, but the map is complex. To prevent smallpox, the ship can be as simple as a sharp needle infected with cowpox. This is all we need to vaccinate against smallpox, if we know how. But first we needed the map; we needed to know about germs, vaccination, smallpox versus cowpox, infections, and so on.

This chapter discusses the maps we have drawn as we tried to understand aging. As we will see, there has been no single consensus map, but rather a myriad of diverse maps and clashing interpretations of those maps. Now we are beginning to coalesce around a map that genuinely explains aging. As for the ship—the tools we need to change aging have become more sophisticated over the past 500 years, until, as of the last decade or so, we are at the cusp of clinical breakthroughs.

Let’s begin by understanding the competing maps we’ve drawn to explain aging. They all contain an element of truth, but none fully solves the riddle.

The Entropic Theory of Aging

At first, it wasn’t clear that aging was even a problem to be solved. The aging of living things is hardly unique. Mountains age, galaxies age, even the universe itself ages. In fact, the second law of thermodynamics states that the entropy of any closed system always increases, that disorder always increases. That’s why after a few years of being left alone, your car won’t start. After a few million years, a mountain range is reduced to dust. And after 11 billion years or so, the sun itself will grow cold. Everything ages.

Life depends on order, structure, and organization. With too much disorder, life cannot maintain itself. And so the mystery appeared solved. Organisms age because the very nature of the physical universe requires it.

A number of specific theories fall under the general heading of entropic explanations of aging. These theories suggest that this basic fact of life—wear and tear—is sufficient to explain the aging process.

Many of these approaches are variations on a theme. The cross-linking theory suggests that all aging is due to molecules becoming linked over time, interfering with their normal function. A similar explanation blames advanced glycation end-products (AGEs) for dysfunction, as glucose molecules bind to protein molecules, causing an accumulation of these waste products and loss of function.

There are a host of other explanations that blame aging on the accumulation of various other waste products, such as lipofuscin, a pigmented lipid product that accumulates in many aging cells.

One particularly tempting variation focuses not on damage to the routine molecules and enzymes, but on the most critical set of molecules in living cells, the DNA. These theories posit that, over time, DNA slowly accumulates damage, reducing the ability to produce critical proteins. As the cell becomes more and more dysfunctional, aging ensues, and the cell finally fails altogether.

All of these theories are based on a fundamental truth: As time goes on, damage occurs. Molecules become linked, waste products are generated, and DNA is damaged. But these theories underestimate the incredible power of cellular regeneration. While it is true that some cells age and fall into disrepair, others remain in full health, living and reproducing without limit, despite cosmic rays, waste accumulation, and a changing environment.

For billions of years, all life was single-cellular, and these individual cells could reproduce indefinitely. Whether these cells aged in some ways is open to debate, but it’s clear that with each reproductive cycle, with each splitting of an older cell into two daughter cells, the clock restarted. Each daughter cell was young and healthy.¹

Life repairs and replaces its components at an amazing rate. If every part in your car were replaced each year, theoretically it could run forever. As we shall see, single-celled organisms do exactly that. This doesn’t violate the law of entropy, because the Earth is not a closed system. Earth is constantly bathed in light and energy from the sun. The sun’s nuclear fusion generates a tremendous rate of entropy, but life uses the solar energy to maintain itself, so that it continues to flourish. There is no physical law that says an organism can’t continue to live and thrive indefinitely, at least as long as the sun shines.

In summary, there is an entire category of theories that try to ascribe aging to entropy, explaining aging in terms of wear and tear, damage, and waste products. Although these theories contain a germ of truth, they don’t offer a complete explanation. Some cells and organisms do succumb to entropy, but others do not. A deeper level of insight is required.

THE JELLYFISH AND IMMORTALITY

The ability to thrive and stay healthy indefinitely can extend beyond single-celled organisms. The Turritopsis dohrnii, known today as the “immortal jellyfish,” apparently has the ability to reverse aging. This invertebrate reverses its aging process until it reaches the protozoan stage. Indeed, it is often called the Benjamin Button jellyfish. Unlike Benjamin Button, however, this jellyfish then begins aging again, repeating this process into, as far as we can see, infinity.

As the authors of a 1996 paper on the phenomenon stated, this reveals “a transformation potential unparalleled in the animal kingdom.”¹ A later article in the New York Times said the finding “appeared to debunk the most fundamental law of the natural world—you are born, and then you die.”²

Animals of the genus hydra also appear not to be senescent. Lobsters, while certainly not immortal, appear to grow and increase in fertility as they age, avoiding the symptoms of senescence that affect most multicellular life.

The jellyfish and the hydra strike yet another blow to the entropic theory of aging.

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¹ Piraino, S., Boero, F., Aeschbach, B., et al. “Reversing the Life Cycle: Medusae Transforming into Polyps and Cell Transdifferentiation in Turritopsis Nutricula (Cnidaria, Hydrozoa).” The Biological Bulletin 190, no. 3 (1996): 302–12.

² Rich, N., “Can a Jellyfish Unlock the Secret of Immortality?” New York Times, November 28, 2012.

The Vitalist Theory of Aging

The notion that aging occurs because we “run out of something” is an old one. Centuries ago, it was called vitalism, and the idea can even be found in writings of the early Greeks, including Aristotle, Hippocrates, and Galen. We age because something in us—the vital spark that gives life—only lasts so long, and then we die because it has run out, leaving us no more than inanimate matter.

Generically, these sorts of explanations are called “rate of living” hypotheses. The most obvious of these explanations was the “heartbeat hypothesis”—that every living creature has a limited number of heartbeats. As you approach that critical value, you age; when you reach that value, you die. This offered a partial explanation for one of the most obvious of aging anomalies: Not every organism ages at the same rate. The thought was that because smaller animals have a more rapid heart rate (or metabolic rate or breathing rate), they age faster than larger animals. In this view, dogs age faster than humans because their hearts beat faster.

Variously called the life force, the élan vital, the vital spark, or simply the soul, this entire concept had been all but abandoned by science in the early twentieth century, because of failures of logic (does a cell have a heartbeat?) and lack of empirical support. But I discuss it here because this general idea, that aging is the result of something running out or running down, is still with us, albeit in modern form.

The central fallacy of ascribing aging to the loss of some critical component—whether a heartbeat, mitochondria, or a hormone—is that we immediately ask what causes aging within that component. If aging is caused by mitochondrial changes over time, then what causes those changes? If aging is caused by having only a fixed number of heartbeats, then what fixes that particular number? If aging were caused by the loss of a key endocrine gland, then what causes that endocrine gland to age?

The Hormonal Theory of Aging

The notion that hormone deficiencies cause aging is still quite popular. The earliest work can be traced to Chinese medicine. In Western medicine the field of endocrinology—the diagnosis and treatment of hormone-related diseases—blossomed in the 1800s. Endocrinology quickly became both mainstream science and accepted clinical medicine. As with many medical advances, however, this was rapidly followed by unfounded claims and wishful thinking.

The most spectacular claims centered around aging in the area of sexuality. These claims involved the use of the testicles (and more rarely, the ovaries) of young animals, which were variously eaten by, transplanted to, or extracted and injected into patients. The most prominent leader in the new field of endocrinology was Charles-Édouard Brown-Séquard, a world-famous physician who practiced in France, England, and the United States in the mid-1800s. He claimed that he “rejuvenated sexual prowess after eating extracts of monkey testis.” Those who adhere to Mark Twain’s suggestion that you should eat a live frog for breakfast, because nothing worse can then happen to your day, clearly haven’t reckoned with Brown-Séquard’s approach to self-improvement!

Truth being stranger than fiction, this approach to anti-aging therapy continued with the transplantation of chimpanzee testicles to human males (and monkey ovaries into human females). Performed worldwide by Serge Voronoff, this became the therapy craze of the 1930s and was so popular that monkey hunting was banned by the French government in their colonies, prompting Voronoff to try breeding monkeys for this purpose alone. Similar interventions became widespread in the United States, using both colored-water injections and goat testicle transplants.

Presently, there is still widespread belief that testosterone or estrogen can actually reverse the aging process. To a degree, this belief springs from the observation that our levels of such steroids fall with age. In most men, this fall is gradual; in most women, it occurs more observably at menopause.

THE VALUE OF GROWTH HORMONES

At an aging conference in Morocco, I was asked if there is any value in using growth hormone to treat aging. “Yes, of course,” I replied. “There is a considerable value, although not in buying growth hormone, but in selling it. It doesn’t do anything for aging, but there is certainly a market for it.” The pharmaceutical firm, which sold growth hormone, did not invite me back.

This common assumption—if hormone levels decline with age, then hormone replacement will make me young again—is not only bad logic, but is contradicted by the medical data. Claims that hormone replacement therapy (HRT) makes some people feel younger are the same as claims made a century ago by those who used monkey testicles, rhino horn, and colored water.

Do hormones sometimes have therapeutic benefits? Yes.

Can hormones ever slow, stop, or reverse aging? No.

The Mitochondrial or Free-Radical Theory of Aging

Perhaps the most publicly well-known explanation of aging is the mitochondrial free-radical theory first published by Denham Harmon in 1972. Free radicals occur naturally, the side effect of metabolism, particularly the metabolism that happens within our mitochondria. As you may remember from high school biology, mitochondria are the “powerhouse” of the cell. Like powerful nuclear reactors, the mitochondria generate large amounts of energy. And, as with nuclear reactors, there’s a considerable amount of waste.

As we burn metabolic fuels (such as glucose), our bodies create free radicals, charg...