Michael Fossel Michael is President of Telocyte

November 13, 2018

Tip-Offs to Rip-Offs?

Filed under: Aging diseases — Tags: , — webmaster @ 11:43 am

Over the past few months, and especially over the past week, I’ve been asked about various internet sites that claim to sell products that affect aging or age-related diseases. In general, the more extravagant the claims, the less likely the claimed outcome. Unfortunately, even the least-credible websites attract sales, which is why they continue. As a parallel case, the classic “Nigerian Bank” scam succeeds because there is always someone naïve enough to believe it. I confess that even when something sounds too-good-to-be-true, I’ve occasionally been tempted to believe it, although I have an absolutely reliable test of credibility. I ask myself if I would I be willing to run it past my wife. That one question has saved me several times, as I can picture the look she would give me if I tried to explain why this one time might be different and this one time it might not be a scam. I can clearly picture the way she would lower her chin and look at me from under her brows as she frowns at my stupidity. I shiver even thinking of it. However, for those of you without a spouse or partner who has the ability to expose blatant foolishness, I offer you the following rules instead.

The credibility of any product is often clearly signaled by the website or advertisement itself. The following warning signals are inversely related to credibility and should tell you that you’re looking at snake oil rather than a credible product. The more of these in the advertisement, the less likely that it works and the more likely it is that you would be better off flushing your money down the drain. Caveat emptor. Here are the warning signals to live by:

  • Multiple exclamation points.
  • Multiple fonts.
  • Multiple font sizes.
  • Multiple font colors.
  • Multiple underlined, bolded, or italicized words.
  • Multiple words entirely in capital letters.
  • Scientific or medical jargon. The size (length or number of web pages or scroll-downs) of the advertisement.
  • The number of movie or media stars whose names appear in the website (especially claims about Oprah Winfrey, Doctor Oz, etc.).
  • The number of universities whose names appear in the website (without citing data).
  • The number of times the names of Nobel prize winners appear in the website (without citing data).
  • The number of times the names of US presidents appear in the website.
  • The number of Fortune 500 firms or their CEO’s whose names appear in the website, for example: Amazon, Microsoft, PayPal, Apple, Google, Yahoo, Bill Gates, Steve Jobs, etc.
  • The number of names of scientific journals dropped into the text without citing data, for example: British Medical Journal, Science, New Scientist, Nature, Rejuvenation Research, JAMA, or New England Journal of Medicine.
  • Pictures of “regular people” (with quotes from them) who purportedly use the product.
  • Numerical or factual errors, grammatical errors, and misspellings.

In addition, untrustworthy websites and advertisements are prone to use particular words or phrases. The use of any one of these might be reasonable, but the more of these words or phrases you find, the less you should be reading (let alone acting upon) the advertisement. Give one point to every use of the following words or phrases. Any product advertisement that has more than five points is almost certainly a scam, pure and simple. Go elsewhere. Here’s the list to watch out for:

  • actually getting younger, age-defying, all I ask you to pay, all you have to do is click the button below, amazing, are you ready, astonishing, back in time, believe me, best-selling, billionaire, blown away, breakthrough, can you believe it, completely indistinguishable, completely safe, confidential source(s), controversial, don’t let this opportunity pass you by, dramatic, elegant, elite athletes, elusive, excitement, exciting, exclusive, famous, first glimmer of hope, formula, fountain of youth,  game-changer, greatest discovery, groundbreaking, historic, Hollywood, holy grail, I can’t promise you, I encourage you to act now, I guarantee you’ll notice the difference, I’d like to send you, I’m giving it away, I’ve reserved in your name, if you act while quantities last, imagine (or imagine if), incredible, insanely good, instant, irrefutable, it’s true, jaw-dropping, keep it a secret, lab-tested formula, latest discovery, legendary, make you young again, maybe you’ve heard of it before, mega-rich, million-dollar, miracle, natural, naturally, next generation, Nobel-prize winning, only one tiny pill, only the start, pay for it later, picture this, powerful, practically everyone, privileged, profound, renowned, research-proven, rich (or richest), risk-free, rushed to your door, secret, secretive, shock, shocking, shock waves, Silicon Valley, single most important, Soviet athletes, special offer, specifically designed, spectacular, spellbound, staggering, stunning, supercharge, supernutrient, taking away all the risk, that’s one…two…three different, the time is now, there’s no catch, thousands of our customers, thrilled, time machine, top-scientists, unbelievable, vibrant, we don’t cut corners, well-established fact, what would you give to, what your doctor didn’t tell you, what your doctor won’t tell you, will work for you, with no risk or obligation whatsoever, without risking a penny, world-famous, would you believe me, you pay nothing today, you’ll be one of the lucky few, you’ll rest easy knowing, you’ll swear, etc.

 

 

October 19, 2018

An analogy: going back in time

Filed under: Aging diseases,Epigenetics,Uncategorized — Tags: — webmaster @ 12:23 pm

I offer my apologies to all of our readers. Work has kept me from keeping up with the next blogs on the biology of aging, specifically those on human disease. My priority is to work to cure disease than update my blog on curing disease, so the blog has moved to the back burner as we move ahead toward FDA human trials.

However, a recent set of emails prompted me to explain the conceptual problem that faces us as we try to cure and prevent age-related disease. As has always been true historically, the major innovations are not technical or incremental, but conceptual and innovative. Major advances in medicine (and other disciplines) hinge upon our ability to open our minds and dispassionately reexamine our assumptions, which are often wrong. Assumptions are usually reasonable, but based on limited knowledge. Looking around us, the world might be flat. Watching the sun, stars, and planets, the universe might revolve around the earth. When we look a little further, however, the world becomes a sphere and the Earth is no longer the center of the universe. The same is true of aging: when we look a little further, we find surprises and a deeper understanding. Too often, we remain content with what might be true, to rarely do we look more deeply to find the truth.

A recent email suggested that even if telomerase gene therapy worked, wouldn’t we still need to consider using “concurrent stem cell therapy, endogenous stem cell boosting therapy, senolytic and NAD+ therapies, caloric restriction, low dose rapamycin, and acarbose “?

The problem is deeper than the question suggests, so I’ll try offering up an analogy.

A time-traveling 21st century physician goes back to 15th century Europe, approximately 6 months before a major smallpox epidemic is due to wipe out most of the population of the local towns. The physician knows that infection (and death) can be reliably prevented by vaccination with cowpox (literally, since the word derives from “vacca”, the Latin word for cow). Specifically, if the physician takes the fluid from the cowpox lesion of (for example) a milkmaid who has active cowpox and smears it on a dermal scratch of a potential smallpox victim, they can prevent smallpox. In short, it’s easy to prevent the epidemic, but only IF we understand understand the pathology.

However, the 21st century physician has become friends with the local 15th century healers, who have a deep knowledge of local herbal medicine. These local herbalists are remarkably observant, keenly intelligent, and have lifetime knowledge and experience with herbs, roots, flowers, bark, etc. They are profoundly competent within their framework, but have no understanding of microbes, vaccinations, or the immune response.

Now imagine an honest and well-intentioned conversation between the local professional herbalist and the 21st century physician and assume that they both respect each other’s knowledge (although the healer still can’t get over their limited assumptions about how to treat disease and cannot understand or believe in microbial disease). Even after the 21st century physician suggests that vaccination would effectively and easily prevent smallpox deaths, the 15th century herbalist persists in suggesting that “yes, that might work, but you still need to use herbs, prayer, incense, and specially made tisanes” to prevent smallpox.

Or to update our analogy, the modern age-researcher is profoundly competent within their framework, but have no understanding of how aging actually occurs at the cellular and epigenetic level. Even after 21st century data suggests that telomerase gene therapy would effectively and easily prevent age-related disease, the modern researcher persists in suggesting that “yes, telomerase therapy might work, but you still need to use concurrent stem cell therapy, endogenous stem cell boosting therapy, senolytic and NAD+ therapies, caloric restriction, low dose rapamycin, and acarbose “ to treat age-related disease.

For my part, I prefer the 21st century.

 

 

July 31, 2018

3.0 Aging Disease

Aging causes disease.

To many people, the relationship is even closer: aging is a disease. The latter view is controversial. Most biologists and physicians would view aging as a “natural process” and contend that “normal aging” is independent of disease. Aging, in this view is not a disease, although it certainly causes disease. They often distinguish between, for example, “normal” brain aging and abnormal brain aging, such as Alzheimer’s, Parkinson’s, Frontotemporal dementia, vascular dementia, and other dementias.

The academic position that “aging is not a disease” is understandable, but ironically inconsistent with normal human behavior. The same academics who argue that “aging is not a disease” are seen to dye their gray hair, undergo Botox treatments or plastic surgery for wrinkles, buy “anti-aging” skin creams, and do everything they can to avoid aging… Judging from behavior (as opposed to academic argument), humans act as though aging were a disease. We go to a great deal of trouble to avoid a “natural process”. So is aging a disease? There is no objective answer. We argue that aging is not a disease, while acting as though it is.

Nor does the argument that “aging is a natural process” validate the position. Aging may be quite natural, but we avidly avoid many “natural processes” because of the risk of death, pain, disability, or fear. Labor pains and neonatal mortality, infections and epidemics, starvation and malnutrition, broken bones and head injuries, and almost everything that modern medicine works to prevent, cure, or treat is a natural process. Simply because a process is natural does not mean that we accept, condone, or value the outcome of such natural processes. Polio infection, smallpox, and tetanus are all natural processes, but these are also diseases, diseases that we put a lot of global effort into eradicating or preventing.

To argue that infection, trauma, genetic disease, or cancer are natural processes is rational, but misses the point and merely results in clinical nonsense. Yes, these are all natural, but are they desirable? No. Precisely the same can be said of both aging and age-related diseases. Natural yes, desirable no.

Arguments about whether or not aging is a disease lose contact with our daily reality. Rather than dispute semantics consider the practical questions: can we do anything about aging and age-related diseases? Most people find both aging and age-related disease to be uncomfortable and worth avoiding – if possible. One of my 94 year-old patients was asked if she would take a pill to reverse aging. “No, I’d rather let nature take it’s course”. I asked about the scar on her sternum: “Quadruple bypass surgery.” I inquired about her swollen knuckles: “Arthritis and ibuprofen isn’t helping any more.” Why had she come to the hospital? “I have pneumonia and I need to be admitted to the… Oh, wait, I see what you’re driving at. I’d take the pill!” In the abstract aging is fine, but the reality becomes a different matter.

If we are to intervene in age-related disease, we need to intervene in the aging process itself. Beneath every age-related disease lies a more fundamental “disease”, that of aging. It is the very genetic and cellular processes that we have addressed in our previous blog posts that trigger age-related diseases, regardless of cell-type, tissue, or organ. Whether we are looking at dementia, arterial disease, joint changes, or weakening bone, in every case we can trace the clinical disease to the changes occurring deep within cells. The gradual changes in epigenetic pattern and the consequent changes in cell functions underlie all age-related problems.

The underlying, common problem in age-related disease is the shortening of telomeres with consequent gradual, but pervasive changes in the pattern of gene expression. These epigenetic changes are reflected in a significant degradation of cell function, particularly in the rate of turnover of molecular pools (internally and externally), the slowing of DNA repair, the decrease in mitochondrial efficiency, and the increase in the rate of molecular damage. In addition, cell aging impinges upon the function of neighboring cells in each tissue, even if such neighboring cells are not as far along on the cell aging spectrum. Although the underlying problem is the same (telomere shortening, epigenetic changes, cell dysfunction), the outcome varies between tissues. In the brain, the aging of glial cells results in neuronal dysfunction and is expressed clinically as one of several dementias. In the case of vascular endothelial cells, the outcome is arteriosclerotic pathology, and is expressed as myocardial infarction, stroke, aneurysm, peripheral vascular disease, heart failure, and other syndromes. In joints, we see osteoarthritis. In bone, we see osteoporosis. No organ is spared. Skin, lungs, kidneys, the immune system, the endocrine organs – all tissues and organs demonstrate age-related changes, loss of function, and diseases peculiar to themselves.

In every case, however, age-related diseases, regardless of cell type, tissue, or organ, share the same etiology: cell senescence orchestrated by shifts in telomere length. In the next several posts, we will explore the diseases of aging, then move on to interventions to prevent and cure the diseases of aging.

Next time: 3.1 Aging Disease, Cancer

July 16, 2018

Aging and Disease: 2.9 Cell Senescence And Tissue Aging

The human body represents a “system” in the engineering sense: all parts (cells, tissues, organs) are interdependent. To understand how the body functions (and how it ages), we may appropriately study individual cells, but we must also study the interactions between cells. We may start by looking at small communities of cells (local, homogenous tissues), but we must then move onwards, looking at how cells, tissues, and organs interact. To give an example, in studying the blood vessels, we can study cells that make up the inner vessel wall (e.g., vascular endothelial cells), we can study other cells in the local tissue (both endothelial and subendothelial cells), or we can enlarge our view to look at how these cells affect more distant tissues (e.g.,the myocardium). We might start by ignoring the interactions with other cells, but if we want to understand most age-related diseases, then we must consider the more distant effects as well.

Initially, we will focus on the cells within a typical tissue. In fact, we will start by simplifying so far as to pretend that a tissue has only one type of cell: an unlikely example in actual practice, but useful as a didactic concept, if only by allowing us to understand what actually happens to a tissue as its cells age.

One overarching concept requires emphasis: failing cells result in failing tissues.

Groups of cells do not fail because of some enigmatic gestalt phenomenon, groups of cells fail because changes in individual cells have effects upon the cells around them, as well as more distant tissues. No cell operates independently, even within a “homogenous” tissue. When cells fail, they not only become dysfunctional by themselves, but they actively interfere with the function of other neighboring cells. To use an analogy, if we have a group of people working together in an organization, then aging is a process in which the organization fails not solely because some individuals refuse to do their job, but because those individuals actively interfere with others around them. To take this analogy back into the biological world, age-related disease occurs because the aging of any particular cell can have multiple effects:

  1. Aging cells no longer do their jobs within the tissue.
  2. Aging cells directly interfere with function of other cells within the tissue.
  3. Aging cells indirectly interfere with the function of more distant tissues.

You might think of a single aging cell as a “sin of omission”, in that the cell no longer performs its normal function; however any aging cell is also a “sin of commission” because it actively interferes with the normal function of other cells as well. To give an example, aging glial cells become dysfunctional in their ability to recycle amyloid molecules, but they also excrete proinflammatory cytokines (and other factors) and thereby interfere with the normal function of surrounding cells that are not senescent. This latter process is generically referred to as SASP (“senescence associated secretory phenotype”) and is typical of most aging tissues.

Aging is not a uniform process, either between tissues or within tissues. In any tissue, not all cells are the same functional “age”. Even in a fairly homogenous tissue, cells age at different rates, have different telomere lengths, and (as a result) differing patterns of senescent gene expression. If we were to measure telomere lengths in aging tissues, we’d find that some tissues have a narrow spread of telomere lengths and others tissues have a large spread, but none of them have all the same telomere lengths. The cells within a tissue have different rates of aging (and different trajectories as well). To see this graphically, see figure 2.9a (adapted from my textbook, Cells, Aging, and Human Disease, Oxford University Press, 2004).

Notice that there are two sorts of variability here: the degree to which any individual cell is “senescent” and the timing of that senescence. As we have noted already, senescence is not an all-or-nothing event, but rather it is a spectrum of dysfunction, due to relative telomere loss and the degree to which the pattern of gene expression has changed. Moreover, some cells move toward senescence quickly, some more slowly, and some with varying trajectories, as shown in figure 2.9a. The result is that if we look at senescence in any given tissue, we see a range of dysfunction. It is not true that all of the cells suddenly flip from normal to senescent, nor is it true that some cells suddenly flip from normal to senescent. In reality, each cell varies in both its degree of senescence and in the rate (or trajectory) of that gradual change. To see this graphically, see figure 2.9b (also adapted from Cells, Aging, and Human Disease).

Cells are part of an extremely complex biological community. Aging cells not only fail to contribute, but can actively and directly impede other cells in that local tissue, as well as having indirect effects in distant tissues. If for example, we look at vascular endothelial cells in the coronary arteries, as some of these cells become senescent, they not only fail to act as adequate “linings” to the artery, they also trigger inflammatory changes in the underlying (subendothelial) cells, Moreover, this local pathology within the coronary artery can result in decreased blood flow (chronically as the vessel narrows and acutely if a thrombus breaks free and “corks” more distant vessels, causing ischemia). In the community of cells that comprise the heart and its coronary arteries, endothelial cell senescence results in a dysfunctional vessel surface (local cells), an atherosclerotic local mass within the vessel wall (the neighboring cells), and, for example, a myocardial infarction in cardiac muscle cells (the more distant cells, that are mere “innocent bystanders”). Cells may be senesce locally, but their senesce may have a dramatic impact on distant cells and the outcome may be fatal for the entire organism. No cell is independent and this is all the more true of age-related disease.

Later in this set of blogs, we will make the distinction between direct and indirect pathology. Direct pathology occurs when one type of senescing cell (for example, the chondrocytes of your knee) directly result in age-related disease in that same tissue (for example, osteoarthritis in that same knee). Indirect pathology occurs when one type of senescing cell (for example, the endothelial cells in your coronary arteries) indirectly result in age-related disease in a different tissue (for example, myocardial infarction when the artery fails).Before exploring these more typical forms of aging and age-related disease however, we will look at another, related type of disease that, while still related to cell senescence and aging, has characteristics all its own: cancer.

First, however, let’s consider age-related disease as a whole.

 

Next Time: 3.0 Aging Disease

July 4, 2018

Aging and Disease: 2.8 Cell Senescence, Changes In Molecular Turnover, Extracellular Molecules

The human body contains perhaps a bit short of 40 trillion cells, which is an impressive number, yet a large part of our body – a quarter to a third, depending how you measure it – isn’t intracellular, but extracellular. This includes not only the fluids within the blood and lymphatic spaces, but the space that lies between our cells, even in “solid” tissue. This extracellular space is just as critical – and as it turns out, just as dynamic – as our intracellular space.

The extracellular space has cells within it, for example the fibroblasts in our dermis, the lymphocytes wandering about in our lymphatic system, and the red and white (and other) cells circulating in our blood streams, but if we ignore all of these cells for a moment, we find that the extracellular space is still a complex place. It is replete with important molecules, including electrolytes and proteins (and many others), and these molecules are continually being “recycled”, much as the intracellular molecules are.

The extracellular space is not a quiet place and certainly not a place where protein molecules can quietly “retire” for a few decades. To the contrary, the molecules come and go, subject to continual degradation and replacement. Aging doesn’t occur simply because molecules “sit around and fall apart”. Aging occurs because molecules aren’t turned over as quickly as we age.

Looking solely at human skin – and then solely at a few of the dozens of important molecules that play a role – we find two well-known molecules that are worth focusing on: collagen and elastin. We will simplify our discussion by looking just at the skin, just at collagen and elastin, and just at both proteins generically, intentionally ignoring the multiple subtypes of both collagen and elastin. We will also simplify our discussion by ignoring the water, electrolytes, immune proteins, enzymes, hormones, and various other structural proteins (keratin, muscle, bony matrix, fibronectin, laminins, etc.) that we might discuss.

Let’s focus on what happens to the collagen and elastin in our skin as we age.

Both collagen and elastin are familiar to most of us, as well as to anyone who has ever watched advertisements for skin care products. Collagen is a long, chain-like protein that provides strength and some cushioning throughout the body, including the skin. It is collagen that keeps your skin from pulling apart, providing resistance to stress. In addition to skin, collagen is also found in cartilage, tendons, bones, ligaments, and just about everywhere else. Elastin is – as the name suggests – and elastic molecule that allows skin (and other tissues) to return to its original position when it has been deformed. You might think of collagen as chain that has strength and elastin as a rubber band that stretches. Collagen prevents too much deformation, while elastin pulls skin back after slight deformations.

As we age, both of these fail. Collagen breaks and our skin becomes more fragile and prone to damage from slight impacts or friction. Elastin breaks and our skin sags and no longer “bounces back”. As both of these fail over time, we form wrinkles, although these are only one of the obvious cosmetic changes that occur. Skin loses both strength (collagen) and elasticity (elastin) over time. Why?

Whether you are six or sixty, your collagen and elastin molecules are steadily breaking down and failing. The difference is not the rate of damage, but the rate of turnover. This is the rate at which molecules – such as collagen and elastin — are recycled and replaced. In young skin, collagen turnover can be as high as 10% per day, but the rate of turnover falls steadily with chronological age, or more specifically, with cell aging. As cells are lost and replaced by cell division, the telomeres shorten, gene expression changes, and molecular turnover slows down. The older your cells, the slower the rate at which they replace damaged extracellular proteins, whether collagen, elastin, or any other protein (such as beta amyloid in the elderly patient with Alzheimer’s disease). No wonder our skin becomes fragile, loses elasticity, and develops wrinkles.
Despite the advertising world, none of these changes are amenable to moisturizers, protein injections, serums, creams, or a host of other “miracle anti-aging products” that tout the ability to erase wrinkles, rejuvenate skin, and restore lost beauty.

There is, however, one intervention that would be effective: to reset gene expression and upregulate molecular turnover, so that key molecules, such as collagen and elastin, are more rapidly turned over, with the result that damaged molecules no longer accumulate, but are replaced more quickly. The key to extracellular aging isn’t the damage, but the rate of turnover. The practical implication is that whether we are talking about collagen, elastin, beta amyloid, or dozens of other types of extracellular protein, we can effectively intervene by resetting gene expression. Whether we are looking at skin, joints, bone, or brains, the potential is an innovative and effective intervention for age-related problems.

Next Time: 2.9 Cell Senescence And Tissue Aging

June 13, 2018

Aging and Disease: 2.6 Cell Senescence, Changes In Molecular Turnover, DNA Repair

Why are we more likely to get cancer as we age?

Not only does the incidence of cancer go up with age, but it goes up exponentially. Why? Moreover, the exponential rise is seen in most species, regardless of their lifespan. It’s not the years, it’s the aging process, regardless of time. Why? The key to these questions lies with the rise of DNA damage as we age. But just as with other kinds of cell damage – free radicals in the mitochondria, for example – the issue is not the rate of damage, but the rate of maintenance. In the case of DNA, however, the key feature to maintenance isn’t the rate molecular turnover, but the rate of DNA repair. DNA is the only molecule that is repaired rather than simply replaced. We replace (i.e., recycle) all other molecules in our cells (and even outside of our cells), but we never replace DNA. Instead, we repair it with great effort and in exquisite detail. DNA carries priceless information in its structure, so rather that just recycling the molecule (breaking it down and building a new molecule), our cells go to enormous lengths (and enormous metabolic cost) to find and repair every single error. Without delving into detail, let’s look at an overview of DNA damage, DNA repair, and the clinical implications for aging cells – and aging people.

DNA damage is continual, as is repair. DNA damage occurs continually due to radiation, oxidation, toxins, viruses, and even spontaneous thermal disruption (even at normal body temperatures) with an incidence estimated at up to 106 hits per cell per day. If unrepaired, the result will not only be a dysfunctional individual cell, but a cell that divides without control, thereby harming (and even killing) the entire organism. Ultimately, uncontrolled cell division is expressed clinically as cancer. Left unrepaired, DNA damage becomes fatal. Clearly DNA repair is critical, and must be both constant and all-but-flawless for any organism to survive.

 

DNA repair is, like most biological concepts, remarkably (almost indescribably) complex. No matter how we discuss it, there will be exceptions, qualifications, and additional intricacies which remain unaddressed in our discussion. We will therefore and of necessity, present a simplified summary of DNA repair, one which presents only a high-level, conceptual view of the cell’s response to a single type of DNA damage (single-base errors), while ignoring other types of DNA damage (e.g., double-strand breaks). With this caveat in mind, we will characterize DNA repair as being handled by four basic families of DNA repair enzymes which have these functions:

  1. Identification: find the damaged DNA base and flag it for removal
  2. Excision: remove the damaged DNA base from the strand
  3. Replacement: insert the correct DNA base into place in the strand
  4. Ligation: link the new DNA base to neighboring bases in the strand

In the aging cell, and correlated with telomere shortening, the expression of all four of these types of DNA repair enzymes are down-regulated. This down regulation is typical of cell senescence and is modulated by the telomere. As the telomere shortens, all four repair processes are down-regulated. DNA repair continues, but at a slower pace. Young cells repair DNA almost instantly, older cells repair DNA but at a more lackadaisical pace. The result is that, at any given moment, older cells are more likely to have unrepaired DNA.

The result is that slower DNA repair – and the rising percentage of (as yet) unrepaired DNA damage – means a higher likelihood that such damage will affect the cell’s ability to control cell division. For example, if the damage occurs to the DNA repair genes themselves or to the genes that are central to the cell cycle braking system (which would otherwise prevent cells with DNA damage from dividing), then the cell may replicate and carry the DNA damage into the daughter cells. The result is a cascade of increasing cell damage and a decreasing ability to control cell division. In short, the stage is set for malignancy, clinical cancer, and death.

We begin to see why cancer rises with age. As cells lose telomere length, DNA repair slows, and the risk of cancer rises. Worse yet, however, each of the steps involved in DNA repair are multiplicative, that is, each step will have an impact on all subsequent steps. So if detection slows and the number of DNA errors doubles, then if excision slows, the number of DNA errors goes up another factor of two, i.e., the DNA errors go up four-fold. When you add in replacement and ligation, the effects multiply one another again, with the result that if we down-regulate all of the steps in DNA repair, the increase goes up exponentially.

Most people assume that cancer rates climb with age because of a longer lifetime means a greater cumulative exposure to carcinogens. In fact, the rate of cancer isn’t correlated with years so much as it is with percent of lifespan. For example, mice have an exponential increase in cancer, just as humans do, despite the fact that the average lifespan of a mouse is about 40 time shorter than the average lifespan of a human. It’s not the years, it’s the rate of DNA repair that determines how fast that exponential curve rises. Ultimately, the deciding factor is not cumulative exposure, but the rate of repair. Mice slow DNA repair over a short lifespan and their rate of cancer goes up exponentially in only two years; humans slow DNA repair over a long lifespan and their rate of cancer goes up exponentially over a much longer lifespan. It’s not a matter of having good DNA repair genes, nor is it a matter of chronology. The deciding factor is neither time nor genes, but gene expression and gene expression is controlled by telomere shortening.

If we take the curves for cancer in mice and humans and overlap them to show not years but lifespans, then the curves become identical. It’s not the years, it’s the rate of repair. If we want to prevent or treat cancer, we shouldn’t be focusing as much on exposure to carcinogens, but on cell senescence. Putting it bluntly, if only slightly simplistically, the reason we get more cancer as we age isn’t a matter of what we were exposed to, but the rate at which we repair the damage that is constantly in play over our lifetimes.

We get cancer because of cell senescence.

 

Next Time: 2.7 Cell Senescence, Changes In Molecular Turnover, Mitochondria

June 8, 2018

Aging and Disease: 2.5 Cell Senescence, Changes In Molecular Turnover, Most Molecules

Filed under: Aging diseases,mitochondria,senescent cells — Tags: , — webmaster @ 3:17 pm

As the human body is composed of cells, so are cells composed of molecules. It is true that the cell encompasses a plethora of organelles (membranes, mitochondria, nuclei, Golgi bodies, ribosomes, etc.), but each of these organelles is in turn composed of pools of various molecules. Just as cytoplasm is a “soup” of molecules, organelles are also collections of molecules. The precise types of molecules, their numbers, and their rates of turnover vary from organelle to organelle. The most common molecular types are lipids and proteins, but with admixtures of other molecules, such as carbohydrates (such as sugars), as well as hybrid molecules, such as glycolipids and glycoproteins. As you’d guess, the complexity not only doesn’t stop there, it barely begins there. To talk of a few simple molecular types is only a fuzzy, naïve sketch of that complexity involved in living cells. We’ll look a bit deeper at t he molecular types, then take a simpler view and focus on the only critical feature in aging cells, namely molecular turnover.

Looking at the cell as a whole, the typical human cell is (by numbers) about half lipid molecules and about half protein molecules. Most of the lipids are in membranes (such as the cell membranes, the mitochondrial membranes, and the nuclear membranes); most (but by no means all) of the proteins are in solution in the intracellular fluid. While the membranes have far more lipid molecules than protein molecules, the proteins are heavier (and larger). So while lipids are more numerous (about 50 x as numerous) than proteins in the membranes, the mass of the lipids and the proteins (as well as glycoproteins, etc.) are about equal.

While the lipids determine how the membrane acts in a general sense, it’s proteins that determine the functional (and the active) properties of the membrane. So while there aren’t as many protein molecules, but what they lack in numbers they more than make up for in their importance to cell activity. What about cytoplasm? About 40% of body weight is made of the intracellular fluid, where lipids are heavily outnumbered. In the cytoplasm, it’s the proteins, the electrolytes, and other molecules that determines the activity.

While proteins (as well as glycoproteins, etc.) come in thousands of types, even the lipids are a complex family. The most commons lipid molecules are phospholipids, but there are also cholesterol molecules (sometimes as numerous as phospholipids) and glycolipids, which are sugar-lipid molecules, especially common on the outer cellular. To make things even more complex, some molecules are complex conglomerates of both proteins and lipids.

That’s the introduction to the complexity, but from our standpoint – aging related disease – the important point is not the types of molecules or where they are, but the observation that all of them – every molecule we’ve mentioned – is in continual flux. All of the thousands of different types of molecules are being actively recycled. This is true whether we look at lipids or proteins, organelles or cytoplasm, intracellular molecules or extracellular molecules, molecules of a single type or compound molecules. They all being actively recycled. To be specific, none of them sit around for your lifetime, but all of them are being replaced on a moment-to-moment basis. With the sole exception of DNA, none of the molecules repaired. Instead, they’re simply recycled.

Some of these molecules are recycled slowly, some are recycled quickly. In the case of aerobic enzymes in your mitochondria, where the damage rate is high, these molecules are turned over rapidly; in the case of come cholesterol molecules, where the damage rate is lower, the molecules are turned over more slowly. While you might guess that “damaged” proteins are tagged and turned over more quickly, the reality is that ALL of your proteins – even those that are 100% perfect – are continually recycled. This turnover, proteolysis, is not just a passive “recycling” but is actively regulated and fine-tuned, and is part of the cell cycle and cell division, gene transcription, and general cellular quality control. Where we once viewed proteins a stable molecular pools that were subject only to “wear and tear”, active molecular turnover has been proven by isotopic studies. There is a basal rate of molecular turnover, specific to each protein and each lipid, which occurs regardless of damage: in any given molecular pool, molecules are degraded and replaced whether the molecule is normal or not. However, the rate of degradation can go up or down, depending on the rate of damage. For example, ubiquitin conjugation to globin molecules is markedly enhanced by denaturation of hemoglobin, so although hemoglobin undergoes “recycling” regardless of damage, the rate of that “recycling” goes up in the case of molecular damage.

Not only does this permit fine control of cell functions, but it is the only way to ensure quality control as well: the faster molecules are turned over, the more likely the molecules are to be undamaged and capable of doing their jobs. As we saw in the last blog, the slower the turnover, the higher the percentage of dysfunctional molecules. If we think of this recycling process as cell maintenance, then the slower the maintenance, the less functional the cell as it becomes clogged with molecules that don’t work.

Proteins, lipids and other molecules are turning over continuously and extensively. The turnover of each individual type of molecule is specifically regulated and varies with cell conditions and over time. The regulation of cell processes is not merely controlled at the transcriptional or translational levels, but is finely regulated at the level of protein degradation as well.

How fast do these molecules turnover? Proteins have half-lives varying from a few minutes to several days. The rate of turnover varies depending upon the protein, available nutrients, hormone levels, and especially by cell aging.

But if molecular recycling requires metabolic energy, then why does the cell engage in molecular turnover at all? They answer is to avoid the accumulation of damaged and dysfunctional molecules. It’s much like asking why a home owner spends money on the upkeep of their house. Both the home owner and the cell must spend (money or energy) in order to maintain function. The more they spend, the higher the quality of the house on a day-to-day basis. The less they spend, the more likely the house (or the cell) is to fall apart.

The key observation, from the standpoint of aging and age-related disease, is that almost every molecule we look at shows a deceleration of turnover as cells age. Lipids, proteins, and other molecules sit around longer. The result is leaker membranes, less effective DNA repair, dysfunctional mitochondria, and a host of other gradually increasing failures in the aging cell.

 

Next time: 2.6 Cell Senescence, Changes In Molecular Turnover, DNA Repair

May 15, 2018

Aging and Disease: 2.4 Cell Sensecence, Changes In Molecular Turnover

Effective maintenance is a product of the rate and the quality of the maintenance process. If we look at a car, for example, the long-term condition of the car depends on how often we institute maintenance (once a month or once every few years?) and the quality of the maintenance procedures (do you replace and repair everything or do you simply change the oil?). If we look at a house, the same questions apply: do you maintain it regularly (every few months?) and do you maintain it thoroughly (do you just vacuum the carpets or do you replace and repair the paint, the pipes, the roof, and the windows?). If we look at a garden, again we find the same issues: how often do you maintain it (once a day or once a year?) and how thoroughly do you care for the garden (do you merely mow the lawn or do you weed, fertilize, trim, and replant?).

Cars, houses, and gardens are not immortal and unchanging. To remain viable, they require maintenance: the more frequent the maintenance and the more detailed and careful the maintenance, then the longer-lasting they are. A well-cared for car, house, or garden can – in effect – be “immortal”. If the maintenance is sufficiently frequent and of sufficiently high-quality, then they appear to resist entropy without any apparent change.

The same is true of cells. Whether we look at proteins, lipids, or almost any other molecular pool, we discover that they are in continual equilibrium: they are continually being produced and continually broken down. There is no molecular pool in the body that remains untouched by the years; whether rapidly or slowly, every molecular pool is in the process of being recycled. The one odd exception is our DNA, which isn’t recycled, but repaired in situ. While we repair our DNA, we simply replace everything else. Even in the case of DNA, however, the molecules that do the repairing are themselves being continually replaced.

The result of all of this recycling is that the cells are generally able to functional. To use the analogy of the Red Queen from Alice In Wonderland, our cells run as quickly as they can in order to stay in one place. Moreover, the faster they run (recycle) the more they are able to stay in one place (fully functional). Or, as the French saying has it “plus ça change, plus c’est la même” (the more things change, the more they stay the same).

The problem comes about when we slow the rate of turnover. The slower this “recycling” rate, the more we tend to see damage. This occurs even if the rate of damage is unchanged. The more critical variable is not the rate of damage, but the rate of turnover. Alas, as our telomeres shorten and our cells senesce, this rate of turnover goes down. We still create molecules – the collagen and elastin molecules in our skin for example – and we still destroy molecules. The rate of creation and destruction is perfectly balanced, so the total number of molecules available at any one time remains unchanged, but the rate at which those molecules are turned over falls with cell senescence.

The upshot is that damage accrues.

Let’s take a typical intracellular molecular protein. A young cell might (hypothetically) have a thousand molecules of this protein and might every day destroy 500 of these molecules and create 500 of these molecules, so that every day it might “recyle” 50% of the molecules. The pool size doesn’t change, but the molecules are changed regularly. An old cell, however, might (hypothetically) have the same thousand molecules of this protein, but create only 50 of the molecules and destroy on 50 the molecules, so that every day it might “recycle” only 5% of the molecules. While the number of molecules available to the cell (1000) remains unchanged, the slower turnover means that any time a molecule becomes damaged, it will be replaced much more slowly. In short, the problem isn’t so much the damage per se, as it is the rate at which the cell maintains itself. The “older” the cell (i.e., the more senescent the gene expression), the slower the rate of molecular turnover and the higher the percentage of damaged molecules (see Figure 2.4a).

To invoke another analogy, if the damage is the rate at which your family produces garbage and the turnover rate (the “recyclilng” rate) is the frequency of garbage pickup, then imagine what happens if you go from once-a-week garbage pickup to once-a-year garbage pickup. Conceptually, this is much the same problem that occurs in cells as they senesce. The solution is not to adjust the rate at which you produce garbage, but the rate of garbage pick-up. To take this analogy back to the cell, the solution is not to adjust the rate of damage (through UV, spontaneous racemization, free radicals, etc.), but to adjust the rate of turnover. Young cells have high rates of turnover and low percentages of damaged molecules; old cells have low rates of turnover and high percentages of damaged molecules.

To take this into a clinical venue, this applies to wrinkles in our skin (in which, for example) collagen and elastin turnover are slower), in Alzheimer’s disease (in which, for example, beta amyloid turnover is slower), and in mitochondria (in which, for example, aerobic enzymes and molecules on the lipid bilayers have slower turnover. In every example of aging and age-related disease – with no exception – we can trace the changes to slower molecular turnover.

For those who might like to get a firmer (and more mathematical) grasp on how this works, consider the following equation and its implications (from my textbook, Cells, Aging, and Human Disease; Oxford University Press, 2004):

If the rate of damage (here arbitrarily 1% of molecules/day) and the total number of molecules in the pool (here 100%) remain constant, but the turnover rate varies (r = the percentage of molecules replaced/day), then the percentage of damaged molecules (X) on day (N) will be XN. At equilibrium, XN = XN-1. This can be calculated as the per cent damaged on a particular day, plus the number of damaged molecules remaining from the previous day (XN-1 times M), minus the number of previously damaged molecules replaced during the past day (XN-1 times r), divided by the total percentage of molecules (M) in the cell. At equilibrium:

Equilibrium protein damage:             X = 1 + [X(100 -r)/100]

If the molecular turnover rate (r) is 50%, then:

X = 1 + 0.5X

X = 2

Given a damage rate of 1%, if the turnover rate were 50%, then at equilibrium, 2% of the molecules are damaged on any given day. If the molecular turnover rate (r) is 2%, then:

X = 1 +.98X

X = 50

Given a damage rate of 1%, if the turnover rate were only 2%, then at equilibrium, 50% of available molecules have been damaged (see Fossel; Reversing Human Aging, 1996; p 260). Turnover rates – whether protein, lipid, or other molecules – have a profound effect on the burden of damaged molecules within a cell, i.e., on cell dysfunction.

In the next few blogs, we will see how this process affects: first, the most common intracellular molecules (2.5), then how it affects DNA (2.6), then mitochondrial molecules (2.7), and finally extracellular molecules (2.8)

Next Time: 2.5 Cell Senescence, Changes In Molecular Turnover, Most Molecules

 

April 24, 2018

Aging and Disease: 2.3 – Cell senescence, Changes in Gene Expression

Changes in gene expression underlie aging and age-related diseases. There is all-but-universal (and equally unwarranted) assumption that both aging and age-related diseases are genetic. We see articles on “aging genes” and “genes that cause Alzheimer’s disease” (or genes that cause heart disease, osteoarthritis, etc.). The reality is that both aging and age-related diseases are not genetic, they are epigenetic.

To get at the difference, albeit in a slightly different context, consider the difference between a skin cell and a nerve cell. These cells have the same genes, but very different gene expression. The difference between a skin cell and a nerve cell is not genetic, but epigenetic. Same genes, different gene expression.

The same is true of aging cells. The difference between a typical young cell and a typical old cell is not genes, but gene expression. The two cells – for example, a young skin cell and an old skin cell – have the same genes, but very different patterns of gene expression. What makes a cell “old” is not gene damage or altered genes, but alterations in the way those genes are expressed. To use the analogy of a symphony orchestra, both young cells and old cells have the same orchestral instruments (violins, oboes, etc.), but they’re playing slightly different scores (Mozart instead of Bach, as it were). Old cells aren’t old because their “instruments” (the genes) are “out of tune”, but they are old because they play a different tune.

This alteration in gene expression underlies all age-related diseases. The reason we have heart disease, dementia, osteoarthritis, osteoporosis, or other hallmarks of aging (including things like wrinkles, that aren’t actually diseases at all), is because certain cells have an altered pattern of gene expression. Same genes, different gene expression.

A growing number of papers have pin-pointed specific changes in gene expression that are present in old cells and old tissues, but they focus narrowly on such changes as “the” important change, then explore how they might address that single, specific change. They see a single “tree” (of a change of expression in single gene) but lack the ability to see the larger “forest” (encompassing the gamut of changes in expression in hundreds of genes). Too often, they view each change as a “cause” of aging, not realizing that each single change is an effect, caused in turn by a more fundamental process: the shortening of the telomere. In fact, there are literally hundreds (perhaps thousands) of such changes, all of which are not, by themselves, causes of disease or aging, but are the results of changes in telomere length. Aging – and age-related diseases – are not the result of one gene, nor the result of the change of expression in one gene, but rather the result of wholesale and subtle changes of expression in many genes, acting in concert. To harp back to the orchestra: the problem is the orchestral score, not the orchestral instrument.

Nor are do such epigenetic changes stop there. As the telomere influences the expression of a few local genes, these in turn influence the expression of more distant genes, which in turn influence genes on other chromosomes. Moreover, there are interactional effects between such genes: gene a1 may affect three other genes, but such “downstream” genes may well be influenced by other genes as well.

Views of aging (or disease) that focus only on one particular gene or gene product (any of the various “x’s” at the bottom of figure 2.3a) miss the complexity of the process. As examples of this, we see human trials that, in the case of Alzheimer’s disease for example, focus narrowly upon particular gene products, such as beta amyloid (or genes, such as APOE4), then express confusion and surprise when carefully thought out interventions (aimed only at beta amyloid) fail to have any impact on the progressive course of the disease. These trials my employ an effective intervention for one particular gene or gene product, but they ignore the expression of other genes and ignore the complex interactions of multiple genes, all of which are undergoing changes in gene expression as the cells age.

Such human trials remove one tree and then wonder why the forest is still there.

Moreover, as we will see, even when you restrict your focus to a particular gene, the problem is not the product itself, but the rate at which it turns over. To stretch our tree and forest analogy, even if you restrict your view to one particular tree, you find that it keeps regrowing. The question isn’t “can you cut the tree”, but “how often you need to recut the tree?” Beta amyloid, for example, is continually being turned over. Simply lowering the amount of amyloid (“cutting the tree”) won’t work – as many human trials aimed at amyloid have shown – because amyloid is a dynamic pool (a “tree that keeps regrowing”).

The problem comes back to the telomere. Not only isn’t it enough to focus on a single gene, a single protein, or a molecule, but even if you use a broader view and look at all the changes in gene expression – modulated by changes in telomere length – you must realize that every single gene, protein, or molecule is dynamic. Alzheimer’s, for example, is not JUST a matter of beta amyloid, but a matter of dynamic turnover in the amyloid pool. To account for the broad changes, you need to account for ALL the gene changes and account for the turnover rates as gene expression changes.

Trying to treat disease is much like trying to treat hundreds of dynamic processes all at once. You can try aiming at all the processes with hundreds of drugs, you can even try to find a drug that will increase the turnover rates of all these hundreds of processes with hundreds of drugs, one-by-one and with interactive side effects. The actual processes that encompass these age-related changes in gene expression are stunningly complex, encompassing DNA methylation, histone tails and other histone modifications, nucleosome positioning, micro RNA’s (miRNA’s), repressor proteins, i-motif DNA “knots”, and probably dozens of other “tools” of our epigenetic landscape, but the details of these processes lie well beyond our current discussion.

The upshot is plain, however. We could focus one-by-one on each of thousands of individual genes, we could focus one-by-one on each of dozens of different regulatory processes, and for each of these thousand genes or dozen processes attempt to develop (one-by-one!) effective interventions, then hope to combine all of these interventions (while hoping there are not interactive side effects) and use them to treat age-related disease by giving thousands of small molecule drugs.

Or, we can simply reset gene expression by addressing the change in telomere lengths.

 

Next time: 2.4 Cell Senescence, Changes in Molecular Turnover

 

April 5, 2018

Aging and Disease: 2.2 – Cell Senescence, Telomeres

Everyone seems to “know” that telomeres have something to do with aging. The internet even has pop-up ads about foods that lengthen your telomeres, with the unstated assumption that will make your younger, or at least healthier. Inquiry shows, however, that not only do most people have no understanding of the role of telomeres in aging, but neither do most researchers, academics, or clinicians. The result is that many have an unfounded faith in telomeres, while others scoff at the idea that they have any value whatsoever. In fact, both groups are naïve, albeit for different reasons.

The contrarian in me is tempted to assert that “telomeres have nothing to do with aging”, just because people expect me to say that telomeres cause aging, which they don’t. Telomeres play an important role. To say that telomeres have nothing to do with aging is inaccurate, but it’s just as inaccurate to say that telomeres cause aging. To give an analogy, we might say that your entire life is determined by your genes, which is inaccurate, or that genes play no role in your life, which isn’t true either. As with most things, the truth is complicated. Were we to be accurate we might say that telomeres play an important role in the incredibly complex cascade of pathology that we see as aging, indeed a critical and irreplaceable role, but telomeres do not cause aging any more than does any other facet in that intricate web of pathology. Aging is not simply telomeres.

Telomeres have a lot to do with how aging works, but telomeres don’t cause aging.

Causation is a slippery concept, despite the assumption that it’s concrete and well-defined. Causation might apply to billiard balls and the laws of motion, but causation becomes misleading when we apply it to multifactorial events, let alone to complex webs of biological mechanisms. This definitional fuzziness is blithely ignored by both those who ask about causation and those who provide an answer.

To move the discussion to history, for a moment, if I asked for the cause of the American Revolution, there might be a thousand answers that were relevant and appropriate (and not necessarily overlapping). We might focus on taxation, representation, the cultural and geographical distance, any number of specific “flash points”, any of several dozen key players on either side of the Atlantic, etc. Pretending there is “a” cause of the American Revolution presupposes that we already share not only a common framework for the discussion, but common assumptions about what constitutes a cause, and (probably) a great many unexamined prejudices as well. In short, most discussions about causation start with the assumptions that already presuppose a narrow answer. Not a good point to begin understanding.

This is equally true of biological causation. For example, what causes cancer? Is it your genes? Is it down-regulated DNA repair mechanisms? Is it cosmic rays, oxidative damage, or “carcinogens”? It depends on what you are asking. All of these contain an element of truth (and supportive data), but none of them are “the” cause of cancer unless you specify what you are asking and what you want to discuss. If you are a genetic counselor, genes are the focus. If you work for the EPA, carcinogens are the focus. You choose to narrow down your focus but doing so prevents an understanding of the broader question of how cancer occurs and why.

In the case of aging we find the same naiveté. The “cause” of aging depends on your assumptions, why you are asking, and how myopically you look at the process. In short, the question often presupposes the answer. As the Romans once said “Finis origine pendet”. The End hangs on the Beginning, or as too often the case (and using more modern phrasing), garbage in, garbage out. If you already presuppose the answer, then why are you asking? To truly understand how aging works, you need to erase your assumptions, step back, and look at the complexity without blinders or preconceptions. Looking at aging without preconceptions about “the” cause is almost always too much to ask.

There is, however, a more practical approach to understanding aging and the complex cascade of pathology that results from the aging process. Rather than looking for causes, look for effective interventions. If we ignore the deceptive question of causation for a moment and focus on intervention, then telomeres come to the center stage. It’s not that telomeres are in any sense the “cause” of aging, but telomeres are, without doubt, the single most effective point of intervention in the aging process and in age-related diseases.

Telomeres lie at the crossroads – from an interventional perspective – of everything going on in the aging cell. To extend the crossroads analogy, all the roads that lead to aging enter the crossroads of telomeres and all the roads leading toward age-related disease leave that same crossroads. The entire road system – that complex web of pathology that we call aging – consists of myriad highways, county roads, local by-ways, and even walking paths, but almost every one of them, eventually, passes though the same crossroads: the telomere.

Telomeres don’t cause aging and they are not the be-all-and-end-all of the aging process, but they do function as a pivot point, a sine qua non of age-related diseases, and – most importantly of all – the most efficient place to intervene.

Having put telomeres in a more reasonable perspective, what DO they do?

In an odd, but almost accurate sense, you might say that no one really knows. That’s true in two senses. The first sense is that there is simply a great deal that we’ve come to know about telomere mechanisms in the past few decades and there is doubtless a great deal more yet to find out about telomere mechanisms. That first sense, however, is true of everything: there’s a lot we don’t know and anyone who thinks otherwise is probably still in their teen years or has managed to get through life with their eyes (and their minds) closed. The second sense, however, is more specific to telomeres, the aging process, and age-related disease. This second sense is worth exploring, if only to realize the specific gaps in knowledge and how they might impinge on our ability to intervene clinically. This involves how telomeres affect gene expression. What we don’t know (for certain) is the linkage mechanisms, despite discussions about T-loops, sliding sheaths, and all the accompanying data involved over the past two decades. It’s still a bit of a black box. What we do know (for certain), is that telomere shortening changes gene expression (see figure 2.2a), and we do know (for certain) that when we reset telomere lengths we reset gene expression (see figure 2.2b).

We know that this change in gene expression is related to overall shortening and that the change in gene expression is more closely related to the shortest telomere than to the average telomere. We also know that all of this has nothing to do with telomeres “unraveling”. As we discussed before, they don’t unravel. It’s merely a pleasant myth based on the shoelace analogy. Telomeres may function a bit like aglets, but the chromosomal shoelace never unravels. Finally, we know that the absolute length doesn’t determine the changes in gene expression: it’s the relative telomere length that sets the pace of cell aging. Again, this is just the most common misconception, and one that causes inordinate confusion among researchers.

Once telomeres shorten, we know that gene expression changes not only on the same chromosome, but on other chromosomes as well. We know that the changes are progressive and subtle if you only look from one-cell-division-to-the-next (with the associated loss of base pairs). Yet over multiple cell divisions and thousands of base pair losses, these changes in gene expression add up, altering gene expression just enough to have effects upon DNA repair, mitochondrial efficiency, free radical production, lipid membrane competency, protein turnover, and myriad other processes that we associate with aging.

As we will see later in this series, it is this loss of telomere length and the crucial changes that it causes in gene expression that underlies aging and age-related disease, as well as explaining many other diseases, such as the progerias. It also explains why, when telomeres are preserved, cells gain indefinite proliferative potential whether in vitro or in vivo: they are, in common parlance if certainly not in fact, immortal.

Finally, all of this explains why, when we re-extend telomeres, whether in vitro or in vivo, we reset gene expression and not only allow cells to become fully functional again but allow the organism to become functional as well. In short, it explains why and how we may prevent and cure aging and age-related disease.

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