Protein Misfolding Theory of Aging

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Protein misfolding is strongly associated with age-related degenerative diseases

Aging and stress, stress and aging—these two human conditions, when paired, can profoundly affect the quality of life. When events go awry, molecular processes take place that, over time, can lead to neurodegenerative disease. At the root of the problem is a fundamental process: protein folding. . . . When proteins misfold, they can acquire alternative proteotoxic states [proteins becoming toxic] that seed a cascade of deleterious molecular events resulting in cellular dysfunction. When these events occur in neurons, the consequences can be devastating. . . . Collectively, these observations provide support for the hypothesis that graceful aging depends on the cell’s ability to counter the effects of stress by maintaining protein folding, which in turn permits appropriate protein function.

To understand the significance of protein folding and how it can go awry (leading to a variety of inherited and age-related diseases, not just neurodegenerative ones), you have to know a few things about proteins and how they fold.

The proper folding of proteins is indispensable to life as we know it. Understanding how it occurs could shed new light on some of the basic mechanisms of life and could pave the way for a better understanding of diseases and how to treat them. By the same token, understanding how protein folding can go awry through misfolding (incorrect folding) could illuminate many aspects of life, disease, and death, showing us how better to preserve life, prevent disease, and delay death.

Recall that a genetic mutation can lead to a protein with an abnormal primary structure and probably, therefore, an abnormal tertiary structure, which could cause disease. Similarly, misfolding in a normal protein’s tertiary structure could cause disease. Here’s another analogy: just as an error in the folding of an intricate origami figure could ruin the whole thing, a misfolding error in a protein could cause disease or death.

Misfolded proteins are implicated in a number of diseases, including cancer, cystic fibrosis, emphysema, chronic liver disease, hypercholesterolemia, nephrogenic diabetes insipidus, and a host of neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease), and Creutzfeldt-Jakob disease (the human analog of bovine spongiform encephalopathy, or mad cow disease). Because these diseases are due in part to protein misfolding—a pathological change in the protein’s conformation—they are called conformational disorders.

Chaperones. In our cells, molecular chaperones (also called heat-shock proteins) are specialized proteins that have evolved to help other proteins fold properly or to help stabilize or refold proteins that have become misfolded. By repairing the damage, the chaperones allow the proteins to regain their functionality. Without this vital cellular function, life as we know it could not exist.

Complementing molecular chaperones are chemical chaperones, which are small organic molecules that serve the same functions, albeit via different mechanisms. The confusing terminology is unfortunate, as the terms “molecular” and “chemical” are obviously relevant to both classes of chaperones. (There are also pharmacological chaperones, but let’s not get into that.)

There are two major classes of chemical chaperones, one of which is called osmolytes. Virtually all organisms have osmolytes in every cell, and they depend critically on them for protection against the damage caused by protein misfolding. Although most osmolytes, such as the amino acid proline, serve this protective role, some others have the opposite effect. Urea, for example, is an osmolyte, but it’s a protein denaturant, as we saw above.

Researches suggest that the preservation of Chaperones’ functionality while we age is closely associated with age related diseases and problems.

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Progerin Accumulation Theory of Aging

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Progerin is a truncated version of lamin A protein involved in Hutchinson-Gilford progeria syndrome. Progerin is most often generated by mutation in the lamin A gene, LMNA. This mutation gives rise to a form of lamin A with a deletion of 50 amino acids near the C-terminus. Lamin A constitutes a major structural component of the lamina, a scaffold of proteins found inside the nuclear membrane of a cell; progerin can not properly integrate into the lamina, which disrupts the scaffold structure and leads to significant disfigurement of the nucleus, characterized by a lobular shape. This interferences with consistency of the nuclear envelope can result in misshapen cell nuclei. The consequence of this LMNA mutation leading to excessive accumulation of progerin which in turn result is the rare premature aging genetic disorder called Hutchinson-Gilford progeria syndrome or simply Progeria.

Recently progerin is implied in the normal aging process as well. The progerin accumulation while we age was attributed to the cause of normal aging process. It has been found that progerin is generated through aging. A Swedish research team has evaluated the inducement of progeria gene and found that as people age more and more “progerin RNA is produced”. It has been concluded that accumulation of progerin in typical cells could cause similar effects to HGPS patients in elder people. In normal human beings, the increase in progerin in the body was reportedly 3.3 percent every year, that in progeria patients it was much higher. This study has convinced researchers of a definite link between progerin and aging who are now trying to establish its connection with the heart disease.

In addition, progerin activates genes that regulate stem cell differentiation via the Notch signaling pathway. which means progerin accumulation could interfere our natural repair and regenerative mechanism and which in turn could cause accumulation of misrepair or unable to repair and regenerate damaged cells and tissues.

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Another reason vitamin D is important: It gets T cells going

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Vitamin D deficiency has been linked to a rapidly expanding inventory of ailments—including heart disease, cancer and the common cold. A new discovery demonstrates how the vitamin plays a major role in keeping the body healthy in the first place, by allowing the immune system’s T cells to start doing their jobs.

In order for T cells to become active members of the body’s immune system, they must transition from so-called “naive” T cells into either killer cells or helper cells (which are charged with “remembering” specific invaders). And, if ample vitamin D is not around, the T cells do not make that crucial transition, a group of researchers led by Carsten Geisler, head of the Department of International Health, Immunology and Microbiology at the University of Copenhagen, found. They draw this conclusion based on their experiments with isolated naïve human T cells.

“When a T cell is exposed to a foreign pathogen, it extends a signaling device of ‘antenna’ known as a vitamin D receptor, with which it searches for vitamin D,” Geisler said in a prepared statement. If there is an inadequate vitamin D level, he noted, “they won’t even begin to mobilize.”

Although this vitamin requirement might seem like a handicap to the immune system, the researchers proposed that the additional step involving the vitamin D receptor might actually serve an important evolutionary function: keeping T cells from ravaging healthy tissue. “Given that T cells are capable of explosive proliferation, the lag phase imposed by the vitamin D [receptor step] may diminish the risk of unwanted immunopathology,” they noted in the study, which was published online March 7 in Nature Immunology (Scientific American is part of Nature Publishing Group).

The body naturally makes vitamin D when the skin is exposed to sunshine (it can also come from eggs and some fish products), but most people in the U.S. are considered to be deficient in the vitamin. In fact, a 2009 Archives of Internal Medicine study found that 77 percent of U.S. adults and teenagers surveyed did not have the estimated minimum healthful level of 30 nanograms per milliliter in their blood. And just three percent of blacks in the survey were getting enough of the vitamin, the 2009 report found.

The new observation of the vitamin’s role in T cell activation could have many implications, including vaccine development (in helping the body to recognize new pathogens) and organ transplant (by discouraging the immune system from attacking a new organ), Geisler noted. Additionally, he added, it “could help us to combat infectious diseases and global epidemics.”

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Unveiling the Secrets of Longevity in Bama

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In the remote and mountainous Bama County of southwest China’s Guangxi Zhuang Autonomous Region, the 2000 census recorded 74 centenarians, a surprisingly large number considering the total population is only 238,000. The ratio of centenarians is 30.8 per 100,000, far exceeding the international standard of 25 per 100,000 for “hometowns of longevity” — centenarian-clustered areas recognized by the International Natural Medicine Society. 90-year-olds in the region total 293, or 123.1 per 100,000, also a noticeably high proportion.

With decades of research, experts have been surprised to find that the ratio of centenarians has not fallen over the past years, while other “hometowns of longevity” all over the world have experienced a tendency for numbers to decline with the invasion of industrialization and modernization. Why Bama remains immune to the phenomenon has caught worldwide attention. Studies have proven that the longevity of the centenarians in Bama is not the product of a mysterious force but is actually the result of long-lasting interactions between many different elements in their lifestyle, heredity, and environment.

Bama County, with a surface area of 1, 976 square kilometers, is inhabited by the different Chinese ethnic groups of Yao, Han and Zhuang. Longevity has a long tradition in the region. During the Jiaqing Reign in the Qing Dynasty (1644-1911), the emperor once presented a poem to a 142-year-old man of Yao Ethnic Minority. In December 1898 during the Guangxu Reign, the emperor awarded a horizontal board, inscribed with “Only the benevolent lives to a ripe old age”, to Deng Chengcai, a centenarian from Natao Village. Today the board has been maintained and well preserved.

Natural Conditions

Located at the 24th parallel of North Latitude and 107 degrees East Longitude, Bama is found at the interface of a semi-tropical and a tropical zone. The average temperature is 20.5 degree Celsius with lowest annual average of 16.9 and highest of 25.9, which is an ideal condition for human existence.

The average annual humidity is 79%. Abundant rainfall throughout the year also contributes to the high ratio of negative ion in the air, which ranges from 2,000 to 5,000 in per cubic centimeter. These levels are work perfectly to strengthen resistance to disease, advance metabolism, alleviate bronchial asthma and stabilize blood pressure.

Meanwhile, the county also has the benefit of being nestled in the picturesque mountains, free from the harm of industrial pollution and chaotic development.

Huang Kele, a 107-year-old farmer still cuts firewood in the mountain, and dislikes the occasional necessary sojourn in the city. In 2000, he went to Nanning, the capital city of Guangxi Zhuang Autonomous Region, to attend a feast held for the centenarians, and he didn’t like the environment and the way people live in the city, “I don’t feel well breathing the air in the city. It’s too stuffy and makes me uncomfortable. ”

Mysterious Microelements

The topography of Bama is in typical Karst style with many mountains and little earth. This condition makes the agriculture-based economy very harsh. Because of this unfavorable natural condition, people have always had to work hard in order to survive. However, the same Karst topography that hampers the growth of plants may have contributed to longevity of humans. Scientific research shows that a great variety of microelements can be found in the earth surface and water in Bama, these elements make their way to the human body through food. Some of these elements play a vital role for human’s health and viability.

Peng Yingao, an expert geriatrist from Xinjiang University noted, “to understand the longevity phenomenon in Bama, it must be noted that the role of microelements is very important. Almost all the microelements held in the water and earth in Bama are the most important for the human body. And the elements that are not needed for human bodies, like cuprum, are found in a very low proportion.”

Bama boasts a number of renowned fountains that hold a great amount of minerals and microelements. In Minan Village, 12 km to the southeast of Bama County, nestles the Minan Fountain, which has the strongest flow of naturally drinkable mineral water in the Guangxi Zhuang Autonomous Region.

Surprisingly local masonry may also have some magic effects. Traditionally, walls are constructed of rammed bricks made from the earth that contains the beneficial elements. People living in these houses may unknowingly benefit from the radioactive energy in the wall.

Surveys show that the food centenarians eat has a rich variety of elements essential for the human body. A normal diet includes staple food like corn, rice, millet, sweet potato, soybean, snailflower bean and green soybeans. The main vegetables eaten by the centenarians are pumpkin seedlings, sweet potato leaves, pakchoi, mushroom, agaric and bamboo shoots. The oil they use is mainly colza oil. Meat mainly consists of local pig, goat, chicken and ducks. However, vegetables rather than meat are the major components of the food in the region. Similarly the food is mostly low in fat and will not accumulate excessive amounts of energy in the body, a factor which is also essential for longevity.

A Healthy Way of Life

Bama people are known for being hardworking. Even senior citizens in their nineties and above still work restlessly and exercise everyday. The mountainous condition poses great obstacles for local transportation. Due to this inconvenience, local people usually have to travel on foot, but the age-old practice has fostered strong character and physique among the people, contributing to the outstanding longevity.

Huang Jiaying, a 106-year-old grandma is very much respected in Suolue Village. She is always willing to offer her help to the fellow villagers who are living under the same harsh conditions. Meanwhile, she keeps working everyday. “It makes me very uncomfortable and a bit stuffy to quit working for even one day.”

Leading a simple but regular life, people there share the same open and optimistic character. The tradition of respecting the old has also helped to form an easy and cozy atmosphere. In their spare time, there are no frequent dinner parties of excessive meat and wine in Bama as in the modern world, and the elderly prefer to relax by singing folk songs.

In recent years, the local government has begun to issue subsidies and conducted regular medical checkups for the centenarians.

A Human Body More Durable Than Wood

According to the local custom, the children of a elderly local more than 60 years old should prepare a coffin. However, many old people in Bama are still fit and healthy even when the coffins prepared for them have long decayed away.

Huangmameijin, a 105-year-old centenarian of Zhuang ethnic minority from Pingan Village, now faces this problem. Her coffin, made in 1958, is falling to pieces upon her touch. “My body seems to be stronger than this trashy wood.” She joked.

A waiting coffin is usually used for the storage of various grains like corn. The 116-old-year-old Pan Nieya from Ganshui Village witnessed the decay of four coffins built for her. When she finally left this world, she was lying in her fifth coffin.

Breaking the Chain of “ Silk Road Longevity”

The longevity hometowns all over the world which have been acknowledged by experts are respectively located in Xinjiang, northwest China, Pakistan, Caucasia in Russia and Ecuador. Experts seem to have found a regular pattern that all of these sites are generally located along the ancient “Silk Road”. But the discovery of Bama has broken the longevity chain along the “Silk Road”.

More amazingly, experts have found that the decline of longevity widely seen in other longevity hometowns has not appeared here. One of the major reasons contributing to this phenomenon is that Bama has not been invaded by modern civilization and keeps its traditional diet.

A unique plan to build a tourist park inhabited by the elderly has been proposed in Bama. But it immediately sparked debate as some fear such “longevity tourism” might threaten the traditional long life of the citizens. “The introduction of modern culture may threaten the longevity chain here,” said Keichi Morishita, president of the International Natural Medicine Society.

source: chinaculture.org

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The Unique Sensitivity of the Elderly

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Elderly individuals have the potential to exhibit sensitivity to a broad range of substances. This is due to internal biological changes associated with the aging body, present state of health, and genetic predisposition. There have been a number of interesting studies elucidating connections between drug sensitivity and the aging body.

As we age our body’s internal absorption, distribution, metabolism, and excretion mechanisms change. These differences arise from (1):

  • Changes in the distribution or transport of drugs/substances as a result of reduction in lean body mass, serum albumin in the plasma, and total body water.
  • Increase in percentage of body fat.
  • Changes in body composition and the function of organs which assist in the metabolism and elimination of substances.

Since most drugs are tested and formulated for young adults, consideration must be given to elderly patients when determining proper dosages. A decrease in blood flow, which comes with age, can cause adverse drug effects in the elderly because it limits metabolic rates and thus decreases the rate of drug elimination from the body. The blood is a transport system, shuttling substances to the liver which, plays the major role in metabolizing foreign substances. This decrease in metabolism can prolong the effects of drugs or even lead to overdose and toxicity if dosages are not reduced. There is a lot of variation between elderly individuals capacity to metabolize substances.

Renal (kidney) function in the elderly is reduced by an average of 50%. This too will limit elimination of substances from the body.

Not only do the rates of clearance (elimination from the body) change as we age, but our response to drugs changes. A few examples are:

  • Increased sensitivity to drugs which depress the central nervous system.
  • Increased sensitivity to side effects such as high blood pressure from psychotropic medication.
  • Hemorrhage from anti-coagulants.

These may even occur after adjustment of dosage accounting for changes in clearance and response. Since the elderly are more likely to receive medication than other groups, it is necessary to define the proper therapeutic dosage for drugs and minimize drug use where possible.

Oxidative Damage

A growing body of evidence is linking the damage caused by reactive oxygen species (ROS) to age-related diseases such as arthritis, muscular dystrophy, cataractogenesis, pulmonary dysfunction, various neurological disorders, and probably cancer (2). ROS occurs naturally, over time, as we age. A study by Orr and Sohal (3) argues that the production of (ROS) in the body is a contributing factor in the reduction of the body’s ability to function on a physical, biological and physiological level and is thus a contributor to aging. ROS is believed to be the main agent of oxidative damage to body tissues, accumulating as we get older. The systems that create ROS also oxidize proteins, which build up as we age. We use proteins to break down unwanted substances in our body as part of the metabolic process. Oxidized proteins are not functional, and as we age larger proportions of our protein pool become oxidized and therefore nonfunctional. The build up of these proteins may also be due to a decrease in the ability to degrade these proteins. These processes may allow for oxidants and harmful chemicals to act upon our body tissues as opposed to being readily metabolized. Concentrations of glutathione, a constituent of metabolism, and its related enzymes are decreased in the gastric mucosa of the aged. This also increases susceptibility to oxidative damage in related tissues (4).

Alzheimer’s Disease

An increased life expectancy for adults in the United States has made Alzheimer’s a common occurrence among the elderly. Over 50% of the U.S’s chronic illness nursing beds are occupied by those suffering from this age related disease. Recent studies have shown that a genetic predisposition and not environmental chemical exposure may lead to the onset of the clinical signs of dementia, which are a trademark of this disease.

Heart Disease

Heart disease in the elderly is the major cause of disability and death. Yet, there is a high sensitivity to drugs as treatment against high blood pressure.

Cancer

There are two prerequisites necessary for cancer: 1) genetic susceptibility; it runs in the family, and 2) environmental insult which triggers development of cancerous cells. The events triggering cancerous cell growth may occur over a long time, making older people more susceptible because of a lifetime of inciting factors. Common cancers among elderly include colon, breast, lung, skin, and prostrate gland. Click here for a description of cancer development.

The aged are also susceptible to skin cancer from direct exposure to UV light. As we age, the three skin layers become thinner and we lose Langerhan’s cells, an immune defense of the skin, from the outer layer. This may be why elders are more susceptible to cancer from exposure to UV light than younger people.

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An Immune Aid for Aging

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An old drug gets new use as an immune boost for the elderly

By Jennifer Chu @ Technology Review, MIT

For many, flu season is simply a nuisance. But for the elderly, it can be like navigating a minefield. With just one exposure, the virus can break through an aging immune system and make the person very sick for a long time. Now researchers at the University of California, San Francisco, have found a drug that may boost immune systems in the elderly, bringing them back to “youthful levels.”

The drug, lenalidomide, is a cousin of thalidomide, the notorious sedative that was found to cause birth defects in the 1950s. Both drugs have been used recently to treat multiple myeloma, a cancer of plasma cells in bone marrow. At much lower doses, scientists recently discovered, lenalidomide can stimulate immune responses in the elderly. The results of their study will be published in the January issue of Clinical Immunology.

“We’re looking at increasing health span versus lifespan,” says Edward Goetzl, director of allergy and immunology research at UCSF. “People have found that somewhere in their fifties, things start trickling down, and we want to keep them up.”

As we age, our immune defenses slowly become less vigilant and slower to respond to attack. A gland called the thymus shrinks, releasing fewer protective T-cells with each passing year. Researchers have found that not only do older people have fewer T-cells, but the T-cells they do have are less active, unable to migrate and patrol the body as effectively as those of young adults. Older people’s T-cells produce fewer cytokines, proteins that help the cells differentiate and proliferate through the body.

Goetzl and his colleagues hypothesized that stimulating production of cytokines could increase the proliferation of T-cells and boost aging immune systems. The team looked through libraries of existing drugs and found five that, at low doses, stimulate the immune system. After more detailed analyses, Goetzl found that only one of the five, lenalidomide, was able both to stimulate cytokine production and increase T-cell proliferation.

The team tested the drug on healthy seniors and healthy young adults. The researchers isolated T-cells from blood samples, and exposed the cells to lenalidomide. They found that the drug boosted the levels of two kinds of cytokines—IL-2, and IFN-gamma—both of which are known to stimulate T-cell production. The team found that the increased levels in seniors matched normal cytokine levels in young adults. They also observed improvements in T-cell migration in the blood samples from seniors.

It will be important to learn what kind of T-cells are producing the additional cytokines, says Janko Nikolich-Zugich, chairman of the immunobiology department at the University of Arizona and codirector of the Arizona Center on Aging. There are many subtypes of T-cells, and certain types decrease in number as we age, while the level of others remains nearly constant. “The compound could be just stimulating something that’s always been there,” says Nikolich-Zugich. “It doesn’t mean this compound might not be something useful down the line—they just have to identify what exactly it might be working on.”

Goetzl is planning a pilot study in which he will administer very low doses of the drug to patients with certain types of leukemia—ones that result in a weakened immune response similar to that seen in the elderly. He plans to monitor their immune performance and their tolerance for the drug to determine an optimal dosage. “We’re thinking of this as a pharmacological probe,” says Goetzl. “If it doesn’t end up being a drug, at least we know we can get cytokine levels up, and we know what to look for in developing new drugs.”

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Our Genome Changes Over Lifetime Could Explain Many ‘Late-Onset’ Diseases Of Aging

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ScienceDaily — Researchers at Johns Hopkins have found that epigenetic marks on DNA-chemical marks other than the DNA sequence-do indeed change over a person’s lifetime, and that the degree of change is similar among family members. The team suggests that overall genome health is heritable and that epigenetic changes occurring over one’s lifetime may explain why disease susceptibility increases with age.

“We’re beginning to see that epigenetics stands at the center of modern medicine because epigenetic changes, unlike DNA sequence which is the same in every cell, can occur as a result of dietary and other environmental exposure,” says Andrew P. Feinberg, M.D., M.P.H, a professor of molecular biology and genetics and director of the Epigenetics Center at the Johns Hopkins School of Medicine. “Epigenetics might very well play a role in diseases like diabetes, autism and cancer.”

If epigenetics does contribute to such diseases through interaction with environment or aging, says Feinberg, a person’s epigenetic marks would change over time. So his team embarked on an international collaboration to see if that was true. They focused on methylation-one particular type of epigenetic mark, where chemical methyl groups are attached to DNA.

“Inappropriate methylation levels can contribute to disease-too much might turn necessary genes off, too little might turn genes on at the wrong time or in the wrong cell,” says Vilmundur Gudnason, MD, PhD, professor of cardiovascular genetics at the University of Iceland director of the Icelandic Heart Association’s Heart Preventive Clinic and Research Institute. “Methylation levels can vary subtly from one person to the next, so the best way to get a handle on significant changes is to study the same individuals over time.”

The researchers used DNA samples collected from people involved in the AGES Reykjavik Study (formerly the Reykjavik Heart Study). Within the study, about 600 people provided DNA samples in 1991, and again between 2002 and 2005. Of these, the research team measured the total amount of DNA methylation in each of 111 samples and compared total methylation from DNA collected in 2002 to 2005 to that person’s DNA collected in 1991.

They found that in almost one-third of individuals, methylation changed over that 11-year span, but not all in the same direction. Some individuals gained total methylation in their DNA, while others lost. “What we saw was a detectable change over time, which showed us proof of the principle that an individual’s epigenetics does change with age,” says M. Daniele Fallin, Ph.D., an associate professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health. “What we still didn’t know was why or how, but we thought ‘maybe this, too, is something that’s heritable’ and could explain why certain families are more susceptible to certain diseases.”

The team then measured total methylation changes in a different set of DNA samples collected from Utah residents of northern and western European descent. These DNA samples were collected over a 16-year span from 126 individuals from two- and three-generation families.

Similar to the Icelandic population, the Utah family members also showed varied methylation changes over time. But they found that family members tended to have the same kind of change-if one individual lost methylation over time, they saw similar loss in other family members.

“We still haven’t concretely figured out what this means for health and disease, but as an epidemiologist, I think this is very interesting, since epigenetic changes could be an important link between environment, aging and genetic risk for disease,” Fallin says.

The research was funded by the National Institutes of Health, Swedish Cancer Foundation, Icelandic Parliament, Huntsman General Clinical Research Center, W. M. Keck Foundation, George S. and Delores Doré Eccles Foundation, Fulbright Foundation and the Icelandic Student Innovation Fund.

The research was reported in the June 25 issue of the Journal of the American Medical Association. Authors on the paper are Hans Bjornsson, Martin Sigurdsson, Rafael Irizarry, Hengmi Cui, Wenqiang Yu, Michael Rongione, Fallin and Feinberg, all of Hopkins; Thor Aspelund, Gudny Eiriksdottir and Vilmundur Gudnason of Hjartavernd, Reykjavik, Iceland; Tomas Ekstrom of Karolinska Institute, Stockholm, Sweden; Tamara Harris and Lenore Launer of the National Institute on Aging, Bethesda, Md.; Mark Leppert of University of Utah, Salt Lake City; and Carmen Sapienza of Temple University Medical School, Philadelphia, Pa.

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Does telomere shortening contribute to aging?

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In humans (and other mammals) telomeres are repeating sequences of nonsense DNA (TTAGGG) bound to special proteins at the ends of chromosomes. They protect the ends of chromosomes from being recognized as double strand breaks by the DNA repair machinery and thus ensure the integrity of DNA. If there were no telomeres, the ends of chromosomes would be joined together resulting in incapability to divide, because our cell division machinery cannot handle this sort of situation. Telomeres also shorten with each cell division because our DNA replication machinery cannot start from the very tip of the chromosome, so parts of the ends are not replicated. This is known as the “end-replication problem” and prevents the cell from dividing indefinitely because at one point the telomeres would completely erode away.

In cells that can divide indefinitely, such as stem cells, telomeres must be maintained somehow. In humans there are two ways to maintain telomere length. One is the enzyme telomerase. It consists of a template providing RNA subunit and a catalytic subunit that extends the telomeres. Telomerase is suppressed as an anti-cancer defense in cells that do not need to divide at all (e.g. neurons) or do not normally divide but are capable of dividing, call these mitotically competent cells (e.g. liver cells). The other way is ALT or alternative lengthening of telomeres, which has a yet unknown mechanism and is expressed in some cancers.

A common answer to the question “what causes aging?” is telomere shortening and the eventual tissue degeneration due to the tissue’s inability to keep dividing once the telomeres have been completely eroded, this is known as replicative senescence. From there follows the simple cure for aging: have telomerase in every cell so that telomeres do not shorten. It is a persistent view and you stumble upon it in every conversation about the causes of aging. The persistence, I believe, comes from the simplicity of the theory and straight forwardness of the proposed solution giving people a sense of control over aging and thus comfort. However, if we wish to abolish aging we must forget our biases and look at the facts.
This review (de Magalhaes and Toussaint, 2004) explores the relationship between aging and telomere length.

There exists a great disparity between in vivo observations of aging and the telomere length:

“No connection exists between mean telomere length and mammalian ageing. Of all studied primates, humans appear to have the shortest telomeres and the longest lifespan.[61]”

“Telomerase overexpression does not alter ageing in mice.[76]”

“There is no correlation between the number of CPDs [cumulative population doublings] cells can endure and the age of the donor.[45]”

Telomeres certainly do seem to shorten in some tissues, but the connection between aging and telomere shortening is on thin ice due to the disparities.

“As with replicative potential, telomere length in vivo is very heterogeneous.[87] Telomere shortening in vivo has been reported in skin cells,[31] blood,[68] and colon mucosa.[30] Other studies found weak correlations between donor age and telomere length,[32] while some studies found no correlation[47,87,88] Moreover, long telomeres have been found in cells from centenarians.[89] Taken as a whole, these results indicate that telomere length varies widely amongst individuals and between different tissues. Although telomere shortening appears to occur in some tissues in vivo, there is little evidence linking telomere shortening to ageing.”

While telomeres do shorten in some tissues, it is unclear whether the cells in vivo let their telomeres completely erode away through divisions and let themselves descend into replicative senescence. In vitro cell cultures of mitotically competent cells seem to have a certain limit to the amount of doublings they can perform (around 50), this is famously called the Hayflick limit. It was thought that this limit also applies to cells in vivo, but newer evidence contradicts this view. Toussaint and de Magalhaes touch upon this in their review:

“In addition, they raised doubts on whether telomere shortening occurs in vivo and whether senescence-associated genes in vitro are also differentially expressed in vivo.[47] In fact, gene expression patterns show differences between in vitro senescent cells and cells from old donors.[48]”

“some evidence suggests that hTERT transient expression can occur in human cell lines when necessary for regeneration,[91] and there is little evidence to suggest that further hTERT expression is necessary in human tissues.[92,93]”

Another article (Rubin, 2002) also speaks about this. The author points out that more careful observations show that healthy cells in vivocan express telomerase when necessary and thus renew their telomeres.

“More careful study, however, has revealed telomerase activity in stem cells and some dividing transit cells of many renewing tissues and even in dividing myocytes of repairing cardiac muscle. It now seems likely that telomerase is active in vivo where and when it is needed to maintain tissue integrity.”

Senescent cells, those that have ceased dividing and exhibit eroded telomeres, however, do appear in mammalian tissues (Herbig et al., 2006). How can this be explained? One theory (von Zglinicki, 2002) tries to explain this. It is argued that oxidative damage which causes DNA damage also shortens telomeres, because any damage in the telomeres is not well repaired by DNA repair machinery. This could act as an anti-cancer mechanism, because as more DNA damage accumulates and the cell becomes more unstable, the telomeres also shorten and prevent the cell from going rogue. This means that DNA damage is the underlying cause of senescent cells in vivo.
If we actually overexpressed telomerase in normal cells the side-effects might be quite bad. I have mentioned before that monkeying around with the pathways of our metabolism is a bad idea. But what would happen? Well de Magalhaes and Toussaint point out that telomerase actually alters the functions of cells and this would probably disrupt the functions of tissues that suppressed telomerase.

“Previously, experimental evidence raised questions on whether telomerase could help tumorigenesis.[77,78] Namely, telomerase stabilizes the telomeres which promotes tumorigenesis.[21,22,79] In addition, some reports suggest telomerase favors tumorigenesis by a telomere length-independent mechanism.[80] For example, a recent study found that hTERT expression in HDFs leads to an up regulation of epiregulin, a potent growth factor involved in tumorigenesis.[81] Another recent study found that telomerase modulates the expression of growth-controlling genes to enhance cellular proliferation,[82] and thus hTERT-immortalized cells may not be functionally equivalent to normal cells. In addition, recent results demonstrate that hTERT-immortalized cell cultures accumulate changes as they proliferate, suggesting caution in the use of such cell lines for tissue engineering.[83] Taken together, these results suggest that telomerase activity promotes tumorigenesis and so using hTERT for therapeutic purposes must be approached with great caution.”

In a previous post I also talked about how telomerase has many extratelomeric functions many of which could promote tumorigenesis, especially if overexpressed. In fact, the mice that overexpressed telomerase had higher rates of cancer than controls.

So it seems that telomere shortening May Not the cause of aging at all, and we may not have to worry about it when coming up with new anti-aging therapies.

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The Longevity Pill?

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Drugs much more powerful than the resveratrol found in red wine will be tested to treat diabetes. By MIT

A novel group of drugs that target a gene linked to longevity could provide a way to turn back the clock on the diseases of aging. The compounds are 1,000 times more potent than resveratrol, the molecule thought to underlie the health benefits of red wine, and have shown promise in treating rodent models of obesity and diabetes.

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A Novel View of Inflammaging

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Inflammaging is a term coined to describe one way in which the immune system runs awry with age. Like a malfunctioning thermostat, the level of inflammatory response is consistently too high, leading to damage to aged tissue:

Inflammation is necessary to cope with damaging agents and is crucial for survival, particularly to cope with acute inflammation during our reproductive years. But chronic exposure to a variety of antigens, especially to some viruses such as cytomegalovirus, for a period much longer than that predicted by evolution, induces a chronic low-grade inflammatory status that contributes to age-associated morbidity and mortality. This condition carries the proposed name “inflammaging”.

I noticed a paper today which contains an interesting take on how inflammation leads to damage. It’s not just the inflammatory response, per this theory, but also the anti-inflammatory systems evolved to shut off an inflammatory response after it has served its purpose. If inflammation is constantly jammed on, then so is the anti-inflammatory system – based on the hormone cortisol – that is trying to shut it down. So you have at once all the downsides of both a constantly active immune system, and an immune system that is constantly damped down: damage from constant activity yet poor immune response when you do need it to fight off disease:

“Inflamm-aging” denotes the up-regulation of certain pro-inflammatory cytokines at older ages, and associated chronic diseases. It is well known that blood levels of cortisol also increase with age, an increase commonly considered to be due to activation of the Hypothalamus-Pituitary-Adrenal (HPA) axis by many non-specific stressors. On the contrary, herein I describe how the activation of Hypothalamus-Pituitary-Adrenal (HPA), far from being unspecific, constitutes: a) the main specific response and counterbalance to “Inflammaging” (‘anti-inflammaging’), b) an explanation for the well known paradox of immune-senescence: i.e. the coexistence of inflammation and immunodeficiency, as well as c) a complex mechanism of remodeling elicited by inflammaging, explaining the long and winding pathophysiological road that goes from robustness to frailty.

Indeed, the phenomenon of anti-inflammaging, mainly exerted by cortisol, with the passage of time becomes the cause of a marked decline of immunological functions, and its coexistence with the increased levels of pro-inflammatory cytokines of inflammaging, ultimately have negative impacts on metabolism, bone density, strength, exercise tolerance, the vascular system, cognitive function, and mood. Thus inflammaging and anti-inflammaging together determine many of the progressive pathophysiological changes that characterize the “aged-phenotype”, and the struggle to maintain robustness finally results in frailty.

The author points to cortisol, and if you look at the Wikipedia entry you will see touches upon a wide range of vital systems in the body. If inflammation is always on, then excess cortisol is constantly trying to turn it off, causing harm along the way.

Fortunately solutions to prevent the immune system from getting into this state in the first place are within sight. If the medical research community makes a sane shift from a philosophy of futile attempts to patch up the end results of aging to preventing and reversing specific degenerations earlier in life, then I imagine we’ll see a range of ways to restore a damaged immune system in the clinic by 2030.

source: fightaging.org

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