With the notable exception of childhood cancer, cancer is a disease of mature or even elderly men and women. Diagnosis of two-thirds of cancers usually occurs after age 70. In this sense, cancer, Parkinson and Alzheimer’s diseases are the plagues of the elderly. The strong association exists between cancerous processes (the spread of cancerous cells) and old age seems to be a major point that is often eluded. Accordingly, with age our tissues change their structure. They dehydrate, lose elasticity and stiffen. The tissues become fibrotic. The old man's parchment skin testifies to this.
It's an old saying in medicine: “Old age is not a disease, but a normal, inevitable consequence of life”. We are born, then we grow up and later on we grow old inexorably. The final stage before the death that awaits us all. And as old age is not a disease, there is no need to resort to a doctor or pharmacopoeia (drugs).
The doctor usually treats the consequences of old age such as Parkinson's or cancer, not the cause of these plagues, i.e., old age. This is a dogma. And as with all dogma, there are many who seek to contend with it. Our pharmacies are full of more or less effective treatments against wrinkles, varicose veins and other heavy legs. Many are trying today to find an alternative to inexorable decrepitude.
Old age, like cancer and Alzheimer's disease, are science puzzles. Our goal is not to preach for an unreasonable lengthening of the lifespan, but to put in common place research hypotheses.
Old age like cancer has a simple explanation.
And there will be, one day, an effective treatment.
This is an opportunity but also a challenge to which society must respond intelligently.
On the corner of the streets of Paris, is written the name of those who gave their name to the street. Usually there is the date of birth and date of death. Few have lived over sixty years. But at all times, there have always been old people, but they were much less abundant than today. Fontenelle (1657-1757) lived almost 100 years. In other words, life expectancy (average length of life) has clearly increased. But the maximum duration of life remained stable.
By the middle of the 18th century, half of all children died before the age of 10, and life expectancy did not exceed 25 years. This increase in longevity has continued at a slow pace during the 19th century, reaching 45 years in 1900. In 2020, life expectancy in most western countries has reached 80 years for men and 86 years for women.
There are many explanations for this gain in longevity. Vaccination against smallpox in the early nineteenth century allowed a gain of nearly seven years (https://www.ined.fr/fr/tout-savoir-population/graphiques-cartes/graphiques-interpretes/esperance-vie-france).
Today, childhood deaths are becoming increasingly rare: 15% of children born in 1900 die before one year, 5% of those born in 1950 and 0.4% of those born in 2015. This drop in infant mortality is the consequence of not only the discovery of antibiotics and vaccines, but also the end of promiscuity. Because of the poverty and promiscuity, the infant slept in the same room that his parents and grandparents. Today the children have their own room and are less likely to be dying of tuberculosis.
More complicated is the reason for the recent and persistent increase in life expectancy. From the 1950s to the early 1980s, effective treatments have been invented for patients struggling with high blood pressure, diabetes and ulcers. However, since this prosperous period, discoveries have stalled.
Despite the lack of real medical progress, life expectancy is increasing by almost 4 months each year. The statistical study of death certificates provides clues to this puzzle. In every developed country, upon death and before proceeding with the burial, the cause of death should be entered on the death certificate.
Collecting and tabulating these data is the prerogative of governments in many countries. This allows cross-referencing of the age with the cause of death, but also with the profession and the sex of the deceased. We can also make comparisons from country to country and see the evolution of mortality from a particular disease.
The advances of the twentieth century have extended the lifespan. The dashing old men have multiplied. But the maximum duration of life has remained stable. Jeanne Calment reached the age of 122 years. We can hope to live even up to hundred and twenty years, but not two hundred years. This limit may be insurmountable.
Managers and executives live longer then hard working men
Various studies carried out by statisticians indicate that it is always better to be a manager than a blue-collar worker. If one wants to live to be old, it is always better to be a woman than a man; to be well-off than to be poor, to be educated than without any training.
While the increase in lifespan has affected all segments of the population, a worker lives on average five years less than an executive and a man on average six years less than a woman. These differences are present in every country.
The explanation for this recent increased lifespan has little to do with the progress of medicine. There are fewer and fewer blue-collar workers. We have grown rich and burn fewer calories than our ancestors. Most of us spend our days in front of a computer. Our ancestors plowed the earth or broke pebbles, come rain or shine. Of course, workers have long been smoking more, or exposed to a larger variety of chemicals than executives. But that explains only a small part of these glaring differences.
The statistics indicates that the difference between the rich and the poor is mostly due to the number of calories consumed. When the work is strenuous, mortality increases, due to heart attack, cancer and Alzheimer’s disease.
In terms of life expectancy, it is better to be a schoolmaster than a Breton fisherman. The worker always ages faster than the executive. This is reminiscent of a physical phenomenon: the fatigue of materials. If a metal is subjected to repeated blows, it will eventually break. Some metals, like cast iron, are more brittle than others like steel. But by repetitious hard physical work that causes trauma, all are at risk of rupture.
When on vacation in Indonesia, one of us visited a sulfur mine on the side of one of the countless volcanoes on the island of Java, where we witnessed the proletarians, bound to the factory, carrying blocks of several tens of kilograms of sulfur on the hillsides. Deformation of their bodies was the consequence of carrying such heavy loads. They looked twenty years older than their chronological age.
Women live longer than men
Another statistical difference, just as glaring, is that women live longer than men, regardless of the country. An American, a Japanese or a Russian woman will usually outlive her husband. The difference between man and woman begins long before birth.
Byrne, J. Warburton , D. Opitz, JM, Reynolds, JF (1987). Male excess among anatomically normal fetuses in spontaneous abortions. American Journal of Medical Genetics , 26 (3), 605-611.)
From the days after fertilization, the risk of a miscarriage is almost 25% higher for a male fetus. The risk of death during childbirth is also higher for male infants.
Ulizzi , L., Zonta , LA (2002). Sex differential patterns in perinatal deaths in Italy. Human biology , 74 (6), 879- 888.
For every disease, the chance of surviving is higher for women than for men. For all types of cancer, women are, on average, affected later in their lives than men. During diagnosis, tumors are less invasive for women. The risk of metastasis is lower among women, resulting in lower mortality.
Young men are more likely to develop Alzheimer's or Parkinson's disease than women.
Worldwide statistics show that though women may be sick, they will suffer from cancer and Alzheimer's on average six years later than men. For a long time the popular explanation has been: exposure to female hormones. Hormones explain the physical and sexual difference between man and woman. But hormones do not explain the difference in life expectancy. There is no data to support that estrogen may prevent Alzheimer's, heart attack or cancer. On the contrary, large doses of hormones seem to promote both cancer and cerebral degeneration.
Kaufman, MJ, Kanayama , G., Hudson, JI, Pope, HG (2019). Supraphysiologic -dose anabolic-androgenic steroid use: a risk factor for dementia? Neuroscience & Biobehavioral Reviews.
And yet this hormonal logic has long been in fashion. At menopause, many women have been prescribed hormone substitutes by their gynecologist. These hormones may have a stimulating effect on vaginal lubrication and libido. On the other hand, we have known since the eighteenth century that hormones are carcinogenic. Castrated women or men do not develop breast cancer or prostate cancer. The daily doses of hormones promote them.
Exit the widespread prescription of estrogen during menopause. But myths die hard. Many women believe that they can slow down old age by taking soy-based phyto-estrogens. They believe that these estrogens are more environmentally friendly and less dangerous. It is only a matter of time for their toxicity to be proven, too.
Age spares no organ and all organs age at the same rate. For the heart we speak of infarct or angina pectoris. For the brain, we have senility or Alzheimer's disease or even Parkinson's. For the lung, we speak of emphysema and bronchitis, while for the liver, it is cirrhosis.
As all organs age at the same rate, scientists have sought a genetic explanation. Only four letters (adenine, guanine, thymine and cytosine) are necessary for encoding a genome. Every cell has the same patrimony, which comes half from the father and half from the mother. The genome is therefore identical in a muscle or a brain cell.
For geneticists, only a genetic anomaly could explain aging. At first glance, everything seemed to prove them right. Some animals live longer than others. Most importantly, there are genetic diseases that result in earlier aging. The best known is a rare syndrome (a few dozen people in the world): the Progeria. These children die at the end of adolescence from cardiac infarction, Alzheimer's or diffuse degeneration. These children also have an abnormal face. The head is unusually large. Children with Progeria do not have hair.
This is a genetic disease and an abnormal gene has been cloned. This gene codes for a protein in the cell nucleus. The structure of the cell nucleus is therefore abnormal. But, it is not just the nuclear structure that is changed. The supporting tissue (collagen) is also abnormal. This explains the multiple malformations including the so recognizable facies.
Lewis, M. (2003). PRELP, collagen , and a theory of Hutchinson– Gilford progeria . Aging research reviews , 2 (1), 95-105).
Likewise, the metabolism of children with Progeria is abnormal.
Rivera-Torres, J., Acín -Perez, R., Cabezas-Sánchez , P., Osorio , FG, Gonzalez-Gómez, C., Megias , D., Andrés, V. (2013). Identification of mitochondrial dysfunction in Hutchinson– Gilford progeria syndrome through use of stable isotope labeling with amino acids in cell culture. Journal of proteomics , 91, 466-477.
The progeria syndrome clearly has a genetic explanation. A mutation in a gene causes the disease. But the biochemical reading is much more complicated. This mutation has many consequences. Some of them are at the level of tissue architecture and metabolism.
It was the discovery of telomeres that put forward the genetic hypothesis. In the 1960s, Leonard Hayflick an American scientist cultivated fibroblasts, cells from the connective tissue extracted from human embryos. He analyzed their proliferation and showed that these cells can divide between 50 and 70 times. Having reached their limits the fibroblasts stop dividing and die. Scientists talk about the Hayflick limit. All cells have a limited lifespan and age before they die. Hayflick is continuing his research by analyzing fibroblasts from elderly subjects. The older the age, the lower the number of divisions. Grown on a Petri dish, cells from older patients divide less frequently. For Hayflick, the explanation lies in molecular biology. Our genes put a limit beyond which the cell can no longer divide. Old age is only the consequence of the degeneration of our genome.
Since the discovery of this apparent limit, this phenomenon has been called into question. Hayflick analyzed supporting cells, fibroblasts, but neglected stem cells. In a Petri dish, these stem cells can divide a much higher number of times. Other scientists are more critical. They think that the Hayflick limit is just a laboratory artifact. The cells proliferate in a Petri dish. When there are too many of them, the laboratory technician detaches the cells from the plastic support, separates them from one another and then transfers a few of them to a new Petri dish. For some, Hayflick's limit would only reflect resistance to these manipulations. After several attacks, the fragile cells would eventually die.
But what reinforced the genetic hypothesis was the discovery of telomeres. Telomeres are located at the end of chromosomes, i.e., at the end of DNA strands. They do not code for a gene and are not expressed. In our language, we say telomeres are non-coding DNA. Their function appears to be to protect the ends of chromosomes and therefore to preserve their integrity. A loss of telomeres would make the chromosomes more fragile and more susceptible to becoming cancerous.
A Soviet scientist, Alexis Olovnikov, in 1971, put forward a new hypothesis: the Hayflick limit would be the consequence of the reduction in the length of protective telomeres of chromosomes. Olovnikov suggested that telomeres shorten until the cell dies. So cell death linked to old age would only be the consequence of telomere shortening. But such a view only remains a hypothesis. What is certain today is that telomeres shorten with age, inflammation and stress. They shorten faster in men than in women.
Aubert, G., Lansdorp , PM (2008). Telomeres and aging . Physiological reviews , 88 (2), 557-579.
There is a fierce debate in biology concerning the role of the telomeres in aging. Large sums of money have been invested up in this research. Many start-ups have tried to lengthen telomeres and thereby block aging. It is a huge failure. Today, there is no evidence that telomere length is no more than a marker of the true cause of aging.
Passos , JF, Saretzki , G., Ahmed, S., Nelson, G., Richter, T., Peters, H., Birch -Machin, MA (2007). Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS biology , 5 (5), e110.
Chemicals that accelerate aging (carcinogens)
Since there are genome abnormalities that cause accelerated aging, there are also chemicals that accelerate aging. Carcinogen is the other name of these chemicals. The tobacco user does not only suffer from lung cancer. Carbon dioxide and other toxic substances, once inhaled, are carried in the blood and cause multiple pathologies. Tobacco users die as much from cardiovascular disease as from lung cancer. Smoking is the leading cause of the myocardial infarction but also of cerebrovascular accidents atherosclerosis of the thighs and legs.
Other diseases of aging are present in smokers, such as Alzheimer's disease or various other cancers (head and neck, bladder or esophagus).
Arthritis or lung cancers are frequent diseases in the elderly. The smoker ages early. It seems older than his nominal status. He dies earlier.
Alcohol is another well-known carcinogen. It is responsible for head and neck cancer and of tumors of the liver and the esophagus. The alcoholic also ages prematurely. His liver hardens like that of the old man and the neurological disorders caused by alcohol resemble senility.
Life expectancy depends on the species. Some butterflies live only for a few hours. They do not even have a stomach because there is no point in eating when in the evening, the butterfly will be dead, just after having reproduced. On the other hand, some turtles can live for two hundred years.
For horses as for men, there are registers. All births must be declared. This dates from the time of the cavalry. The military wanted to know who owns a horse, so they could requisition in wartime. Even today, recording is necessary for the cause and date of the horse's death. This allows knowing the age of the animal at death with certainty. The aging horse, that is to say between twenty-five and thirty years old, suffers from diseases identical to humans. He loses his teeth, bleeds easily, becomes senile and develops cancer. An English horse aged 62 years died of old age.
Life expectancy depends on the size of the animal. The little mouse lives on average two years, the rat four years, the dog a dozen years, the horse 25 to 30 years and the big whale almost 40 years.
The number of heartbeats varies little from one species to another. For mammals, the heart can beat between 100 millions and 1 billion times. The heart rate varies. The heart of a mouse, at rest, beats 600 to 700 times per minute, while that of a whale beats 15 times. The smaller the animal, the greater is its heart rate and the shorter is its lifespan. The life expectancy increases as the heart rate slows.
Zhang, GQ, Zhang, W. (2009). Heart rate, lifespan , and mortality risk. Aging research reviews, 8 (1), 52-60.
A link also exists between heart rate, weight and metabolism. The heavier the animal, the slower the heart rate and the lower the metabolism and the longer is the life expectancy. A mouse burns intensely. She has little fat. If she is not fed for two days, the mouse will die. As for the whale, it can make long trips without feeding. Its body is rich in fat. Kleiber's law establishes a link between metabolism and body weight. It was discovered over 80 years ago now. Life expectancy will be longer as the heart rate is slow or the energy expenditure per unit of weight is low.
The study of animals gives us further information. There are animals that do not age. They can even rejuvenate. Turritopsis nutricula (Cnidaria Hydrozoa) is a jellyfish. Like any animal, birth of this jellyfish occurs from the union of sperm and ovum. It grows in the form of an asexual polyp that is attached to a rock at the bottom of the sea. At puberty, this polyp transforms into an adult jellyfish detaches from the rock and will be carried by the current. If the environment lacks food, the jellyfish can regress into a polyp, lose its sexual characteristics and “rejuvenate”.
Piraino , S., Boero , F., Aeschbach , B., & Schmid, V. (1996). Reversing the life cycle: medusae transforming into polyps and cell transdifferentiation in Turritopsis nutricula ( Cnidaria , Hydrozoa ). The Biological Bulletin, 190 (3), 302-312
This jellyfish is not eternal because in real life predators eat it, but it nevertheless does not age. Like the prokaryote that divides into two identical bacteria and does not age, there are potentially immortal beings.
The reason behind the immortality of this jellyfish remains a deep mystery. Geneticists praise, without proof, the exceptional genome of the jellyfish. We would tend to make a completely different hypothesis. The jellyfish flask has no skeleton. The vast majority of the molecules that compose it are water molecules. As proof, when it runs to the beach, the jellyfish will dry up and almost disappear in the sun. It cannot stiffen and therefore cannot grow old.
Marc Henry, "The state of water in living systems: From the liquid to the jellyfish", Cellular and Molecular Biology (2005), 51: 677-702.
Aging is after all a very predictable phenomenon. Pregnancy lasts nine months, the child walks at one year and can read at six. White hair appears around 35, presbyopia at 50 and menopause around 55.
Age is visible. The toddler's skin is plump and hydrated. Over the years, the skin dries up. The old man's skin is hard, parchment covered with superficial vessels, which bleed at the slightest trauma. Drying is not a process specific to the skin. Internal organs loose flexibility and become hard. This loss of flexibility is not specific to human and veal is more tender than the old meat.
Often in biology, the definition varies according to the expert. For the geneticist, old age is an anomaly of the genome. The Progeria, a genetic disease where the patient age quickly is an example. These adolescents die of cancer or of Alzheimer’s disease. For ecologists, aging is the consequence of the poisoning of the environment. For cosmetic surgeons, it is the tissue structure that collapses. It is thus necessary to tighten the tissues that are loose. These experts all see a facet of the truth.
We will have to reconcile the different perspectives. The clinician and the biologist do not see the picture from the same angle. The former examines the patient and the latter deals with patient’s cells.
Cells are the building units of any tissue. This is the central dogma of biology. Juxtaposition of cells leads to the tissues.
These epithelial cells are fed by the underlying blood vessel present in the dermis. Between the blood vessels and the epithelium lies the most common protein in the body: collagen. Its name reflects history. The ancients extracted collagen from tendons to make wood glue. The fibers bind together to support the overlying epithelium.
Among young people, the hydrated collagen strands slide with each other. , since the tissue is supple. When collagen ages, there is formation of fixed bridges between the different strands, which can no longer slide. The fabric therefore loses its elasticity and becomes rigid. The glue freezes.
The gerontologist observes that the old man has lost his elasticity. The collagen can no longer slide and therefore breaks. This is an explanation for development of wrinkles, but also hernias and other aneurysms. The tissue breaks. The skin becomes like parchment paper and the tissues stiffen. This loss of flexibility affects all tissues. The wrinkles which make the fortune of cosmetic surgeons are a direct consequence the decrease elasticity of the skin.
Tissues lose their elasticity because the collagen has become clogged with sugar. Maillard's reaction has been described in the nineteenth century. If you cook meat over high heat, the meat becomes dehydrated. There will be black deposits on the frying pan. They are an assembly of proteins and carbohydrates denatured by heat. In our body, proteins and carbohydrates have cooked at 37 degrees for a long time. Chemists speak of Maillard's reaction, biologists of glycation products and women are concerned by their age spots . Sugars build bridges between proteins changing the conformation of collagen and make it brittle. This is a key point in cellular aging.
The doctor also knows that old age is the link between all pathologies. The older the patient appears, the more at risk he is. Anyone who looks much older than the age written on his identification card will sooner have a heart attack, cancer or Alzheimer's disease. He will quickly draw one of these pathologies at a fatal lottery.
The biologist takes tissue samples from a young animal and compares it to that of older animals. He will confirm what the clinician has observed. The architecture and composition of the tissues has changed. This biologist can color the collagen fibers and see the breaks in these filaments. He will also see that inflammatory cells have infiltrated the tissue drying it out. The muscle will be depleted. There will be fewer muscle cells. The tissues will be infiltrated by lymphocytes, white blood cells. The liver will be lacerated with collagen fibers that did not exist there in the young. The arteries will be clotted with deposits of cholesterol laid on an underlying inflammation. This diffuse inflammation results in an increase in C Reactive Protein (CRP) and Sedimentation Rate (ESR).
Sang, Y., Fung, E., Xu, A., Lan, HY (2017). C - reactive protein and aging . Clinical and Experimental Pharmacology and Physiology , 44 , 9-14.
In aging like in inflammation, cancer and Alzheimer there is a Warburg effect.
Wallace, D. C. (2005, January). Mitochondria and cancer: Warburg addressed. In Cold Spring Harbor symposia on quantitative biology (Vol. 70, pp. 363-374). Cold Spring Harbor Laboratory Press.
Biochemical analyzes show that old mitochondria are less efficient. The membranes of the mitochondria have stiffened and energetic efficiency drops.
Navarro, A., Boveris , A. (2007). The mitochondrial energy transduction system and the aging process . American Journal of Physiology-Cell Physiology , 292 (2), C670-C686.
The reason of this facet of the Warburg effect may be simple. Oxygen diffuses poorly in the human body. We are made up of 70% water and the oxygen concentration is almost zero within a millimeter of the capillaries. The presence of these bridges between the collagen fibers reduces the diffusion of oxygen, which play the same role as a plastic bag that blocks breathing.
Aging tissues therefore have not enough oxygen. The mitochondria are malfunctioning. The tissues will therefore switch to the Warburg effect and ferment.
As the mitochondria works at low efficiency, the cell will open the floodgates. The aging cell will not burn efficiently. It will release its waste, like lactic acid in the blood stream. This is the reason for the inflammatory syndrome.
Other molecules that cannot be burnt will be released into the cellular environment and will accumulate around the aging cells; these are the amyloid plaques of Alzheimer's disease or the Lewy bodies of Parkinson's disease.
Still others will stay in the cell and allow it to divide. It will be the tumors.
We are gradually seeing the commonalities between cancer, Alzheimer's and simple aging. Cancer and Alzheimer's are usually diseases of old humans or animals. The faster the animal ages, the sooner it will develop tumors and senility. These are the same chemicals that induce both early aging and cancer and Alzheimer's disease. During old age, but also in cancer or Alzheimer's disease the tissue is hard and inflamed.
History has divided medicine into specialties. The gerontologist treats the old man, the oncologist: the cancer patient, the neurologist: the Alzheimer patient.
But everything suggests that it is a continuum. Aging is a decrease in energy yield. This decrease is increased in cancer and Alzheimer’s disease. Cancer disease is a consequence of aging and Alzheimer's disease too.
During old age, the energy yield decreases; to judge only by the physical performances. In old age, reduced energy yield causes this diffuse inflammatory syndrome. The skin becomes dehydrated and hardens. As in cancer, new vessels appear and bleed easily.
We have a complicated puzzle to dissect to understand it. The aging body dries up, hardens, and energy efficiency drops. Back to our jellyfish, it does not age because it is full of water. Collagen fibers are in this case rare and distant.
In mammals, collagen fibers are much denser. Debris from the sugar sticks between the collagen strands that can no longer slide with each other. These fibers are at risk of breaking. But these bridges between collagen fibers have another consequence. They prevent the diffusion of oxygen. The old cell breathes badly. The cell burns less efficiently and goes into synthesis cause inflammation and its consequences: cancer and Alzheimer.