Hi, more musings…
I have to do simpler, more direct and practical blogs. Some of you asked about osteoporosis for example. I got waylaid. I swear it is on the list right behind the topic of exercise. Meanwhile, I have been thinking a lot about ageing. Of course, it is highly relevant… related to, but not as difficult as the concept of differentiation and growth.
For Context, imagine in the beginning “G-d” speaks to Moishe, his busy-body part court engineer, part court jester, “Moishe, I am a busy “G-d.” I want you to create a code of sorts. I want all of the different life Domains, Kingdoms and Phyla to be created from the exact same code. The backbone of the code has to exist of only four different molecules, each of which can hold hands with any of the other to form a chain (chromosome). The latter will match up to only one other chain composed of the same four molecules, but the cross linkages between chains can only occur between two of the same matched molecules out of the above four.” Moishe says, “you mean insects, sea grass, birds, bacteria, whales… all from combinations of the same four molecules? Don’t fuck with me, G-d.!” “Moishe…careful,“… ”Sorry, on it.”
Moishe was indeed very clever. He figured he could create an alphabet, wherein each letter consisted of a specific combination of any three of the four molecules. He called each of these a codon. Certain combinations of codons (genes) formed the template for messenger molecules (RNA) which would end up creating proteins. He crowded all this information into a tight package called a nucleus (bacteria excepted). Moishe consulted with an angel friend of his who eventually made a killing in one of those apps which organize your closets. The nucleus was like a cramped filing cabinet, with tall thin vertical draws tightly closed. But the cabinet was specially designed. It is kinetic. It can twist and turn, the draws can magically pop open exposing more interior draws. The draws themselves could twist and fold and create three dimensional structures which would selectively expose key parts to allow for selective exposure and activation of certain genes to make RNA. The RNA would move outside the nucleus and form a template of sorts on an anvil (ribosome) allowing the appropriate amino acids to hold hands and become a protein.
Moishe was very self-satisfied. But there were bumps along the road. For example, for some of the living creatures, he realized he would need more amino acids for protein formation than he had planned for. He couldn’t redo the nucleus thing, so he shrugged and labeled the remaining amino acids “essential”, created them in nature and had them ingested. Then he really got into trouble.
Long story short over time some creatures evolved, but others actually devolved. Moishe had a prolonged tryst with another angel and when he finally checked in things were operating in unforeseen ways. He found two visually identical butterflies, but when he looked closer they had totally different genes. In fact, they were different species which somehow had adopted in the same fashion using different genes. But things really got crazy. Man had about 25,000 of these genes, but the mouse had 30,000. A species of rice had 51,000 genes. The mustard plant has as many genes as a human. What the F***???
Moishe had special humans, called scientists, look more closely into matters. (He, like G-d was busy). Lo and behold, the genes consisted of two parts, one which actually was involved in the manufacture of the proteins (called “exons”), and surprisingly, a much longer chain of codons, usually in between the exons, not doing apparently anything. They were called introns. The introns were initially treated by the scientists like an appendix, i.e., an ancient vestige just hanging around to eventually atrophy and disappear. I thought (honestly) BULLSHIT. There is just too much of these introns to be useless. At the very least they would have to affect the shape of the gene and hence the chromosome itself (and they do).
These chromosomes actually have a three-dimensional shape and as a lock and key, have to be presented in space and at the right time to be effective. The intron was pivotal in informing that shape even if it was gene -poor. Also, the human scientists eventually did discover some genes on the allegedly silent introns, which ultimately produce proteins which can stimulate or inhibit the business end of the chromosome, the exon. (These suppressor and enhancer genes, by the way, play a role in certain cancers). Also, the many interactions within a cell occur at dizzying speeds…thousands of reactions per seconds. This latter was totally lost on the scratchy loud chalk marks of our college and medical school class rooms.
Remember when President Ronald Regan couldn’t balance his budget by 43 billion dollars. He presented himself as a fiscal conservative and in those days, people thought 43 billion was serious change (Ha, ha!). Anyway, he clarified the entire problem with “hey, we will fix it later.” It kind of reminds me of a huge part of the missing puzzle scientists are trying to figure out: embryology.
Yes, embryology. If all the cells in a human originate from a single cell, and if all cells have the same code residing in the nucleus, how does differentiation occur? How do they change? Also, if all the cells in, let’s say, heart muscle are essentially the same, does that explain how do they “know” how to “hold hands” and form a structure?
Somewhat Ronald-like scientists’ kind of shrugged and concluded it must be something called epigenetics. This is the sum of genetic material including RNA and proteins outside the nucleus residing in the cytoplasm. The latter is the fluid within the cell and starts out coming exclusively from Mommy. Sperm is pure gene, but the egg contributes a host of additional information in the cytoplasm. Also, many different chemicals find their way into the cytoplasm during different stages of development. The study of epigenetics is quite real, but like Regan’s budget, leaves a lot to be explained. Clearly, it has a lot to do with informing the nucleus to perform different tricks in a timely fashion.
So, this started with the question what is the nature of ageing. My rambling prologue was described as “context.” Clearly, it’s a lot harder to get to a fully formed creature from a role in the hay than to age, but you can’t fade, unless you get there in the first place, and ageing must have something to do with undoing the growth and differentiation which antedated it.
One more point of context… Ask yourself “what is the definition of life?” What are the characteristics an entity must have to be alive? (We are not talking philosophy or law here). It’s a great exercise. If you want to skip it, head on.
For an entity to be alive it must have all of the following characteristics:
1) Growth and development
2) Reproduce offspring
3) Heredity of traits
4) Homeostasis (the ability to maintain itself).
(5) Metabolism (the creating of building blocks and the formation and efficient use of energy).
6) Physical structure and
7) The ability to respond to the environment.
What is not included in this definition, but should be, is the ability to die. And the death must be on two levels.
The entire organism must die. If there were no death, adaptation of the species to the environment would be far less efficient. Linemen in the NFL wouldn’t weigh over 300 pounds because there would probably be far fewer births; and social security would really bottom up. So, a healthy society needs death.
The second level of death is cell death. The cells in our body must die for the entire organism to thrive. This is called PD or programmed cell death. When a cell dies it is called apoptosis (Greek for something). Of course, the dead cell is replaced by a spanking new functional cell that mysteriously originated from a progenitor stem cell. These are the cells which are hanging around, ready to spring into action to replace dead cells. We replace our blood cells in weeks. Our skin and the lining of our intestines in months. We even replace a few percent of our brain and heart cells over the course of a year.
Ageing like death exists on two levels. We know what it is to age… at least most of my patients do. You lose a step or two running for the bus. Where did I put my wallet? How come my belly sticks out if I am eating less and am active? Shit, shit, shit!!!!! Well, we will discuss this in further detail next blog, but the take home point is the second level of ageing is decrease in cell death and less robust cell replacement. CELLS AGE WHEN THEY REFUSE TO DIE. This is called senescence. These old cells run out of steam, don’t metabolize efficiently and produce fewer and substandard proteins. Some of these proteins are supposed to function as enzymes, i.e. organic catalysts which speed up cellular reactions.
There are seven pillars of ageing. Someone figured out that the average human could theoretically go to 115 years of age. Others have noted that people who live longer, also suffer far fewer illnesses. Maybe by scientifically focusing on ageing, rather than specific diseases, we will prevent those diseases in the first place. Interesting hypothesis. But, back to the pillars…I will close by itemizing them as a teaser, and next blog we will discuss if we can manipulate these pillars to slow down the ageing process.
The pillars of ageing are:
Disorders of metabolism
Disorders of protein formation
Poor quality and/or quantity of stem generation.
Meanwhile, remember eat a Mediterranean diet, get enough sleep, do at least 150 minutes aerobic exercise a week, actually put some thought into reducing stress…and listen to your doctor, but don’t think of him/her as a role model.
Ha! Well, part II of ageing coming up. Hopefully followed by exercise and osteoporosis.
Wouldn’t you know it? No sooner than we review the subject of aspirin, then yet another large study is published and reviewed by the Times. So, “back to the drawing board” but not really. The New York Times article was a well written, good review of the New England Journal article, but still needs clarification.
The data base of the original article can be reviewed on-line. The authors screened 80,000 older adults, but only used 20,000 for its study. A large majority of typical adults were not included because they were not healthy enough… but, they were representative of an average patient. The 20,000 included had kidney function much better than the average adult. The kidney is a favorite target of ageing and is reflective of the overall cardiovascular health of a person. So, these were super healthy older adults. Within the 20,000 there were many subgroups which did benefit from aspirin, for example, cigarette smokers. So, if you are super healthy and have a low risk of dying, it is not surprising that taking any medicine will backfire.
Some of you have called asking if the aspirin should be continued. As in the treatment of cholesterol, aspirin use for “primary prevention” (i.e. taken to prevent a first cardiovascular illness) is based on clinical assessment of risk. Most of my patients of a certain age have had noninvasive imaging of either the arteries in the neck or the coronary vessels surrounding the heart. These pictures add enormous statistical heft to our ability to assess risk. For some of you, the presence of significant imaged atherosclerosis of the large vessels has put you into a higher risk category, and I have therefore recommended aspirin use. The reasoning is that if the risk of a first heart attack is as high as the risk of a second heart attack following the first one, we should treat more aggressively and therefore add aspirin.
Full disclosure, there has been no major prospective trial using aspirin in patients who are at high risk from imaging data of the coronaries or carotid arteries, but average to low risk from other parameters like cholesterol or blood pressure. It is only my best guess. Consequently, if aspirin use is not tolerated in this group of patients, I have zero objection to discontinuing its use.
Finally, there have been a lot of questions regarding aspirin dosing and weight. If you are under 154 pounds, one baby aspirin is fine. It is unlikely to work over that weight (for primary prevention vs stented patients, stroke victims etc.) and a full dose aspirin is suggested.
There is a growing body of evidence that tiny dose aspirin taken twice a day is as effective as one adult aspirin once a day for primary prevention. The basis for this is, as stated in a previous blog, that even if the platelet cells are poisoned by aspirin soon after taking it, the body replaces 20% of the platelets throughout the day, and small doses of aspirin twice a day will cover the stickiness of the new platelets.
So, life is complicated, but also fascinating. The recommendations published by the various medical professional societies are called “guidelines” for a reason. They are often beacons to aim for, but they do not preclude keeping your eyes on the ground to avoid falling into manholes.
PS… Will try another topic tomorrow.
We were to discuss interesting aspects of exercise, but, as will I suspect often occur, there have been several of you who are interested in important issues you noticed in the Press. The leading candidate today is Aspirin.
The health reporters of the New York Times noticed an article in The Lancet, a wonderful British journal specializing in internal medicine and relevant social issues. I read the Times article. The upshot is that the researchers did an analysis of prospective randomized trials of aspirin use in people without any history of heart attack or stroke. The individual trials, to prevent bias, followed the patients from the initiation of the trial forward (prospectively) rather than risk “cherry picking” data, by looking backward in time (retrospective) to already catalogued events. The different arms of a trial are randomized to be sure the subjects in one arm are as identical as possible to he subjects in the other arm. The endpoints were cardiovascular disease including stroke and heart attack, as well as death from cardiovascular disease. The Times reported that “baby aspirin” i.e. 81mg worked well enough in people weighing less than 154 pounds but one had to use a full adult aspirin in patients weighing more than 154 pounds. Most of the patients under 154 pounds were women, and over were men. I decided to check the original article in the Lancet to “get in the weeds.”
First one has to realized that the odds of getting a stroke OR heart attack, having had one OR the other already, are vastly higher than getting a stroke or heart attack WITHOUT any prior history of either. Trials of prevention after having had an event are called secondary prevention trials, and trials in patients without history of an event are called primary prevention trials. In primary prevention trials, often, large numbers of patients are needed, and, also, have to be followed for a long time before meaningful conclusions can be drawn.
So, in primary prevention trials out of 15,000 patients the difference between placebo and low dose aspirin in patients under 150 pounds was statistically favorable to low dose aspirin, but number of people protected was only 200 out of 15000. The low dose lost its effect on individuals weighing more than 154, who did benefit from full dose.
It is really important to distinguish aspirin use in primary trials from other situations. For example, if one is in the throws of a heart attack a single aspirin can reduce the mortality rate by an amazing 30% in an aspirin naïve patient. Use of aspirin is felt to be imperative in anyone who has had a stent to prevent stent thrombosis, or in anyone who has actually had an MI or stroke, particularly in the first year of the event.
There are three interesting controversies arising from this trial:
Most of the aspirin preparations were coated tablets, and these had a tendency NOT to be as effective as uncoated tablets. Could exclusive use of uncoated tablets have a different result?
The authors also looked at some secondary prevention trials in patients who actually had strokes. There is a strong suggestion that VERY low dose twice a day aspirin, or higher doses twice a day in heavier individuals, might be more effective than once a day aspirin. Aspirin irreversibly binds to platelet cells in the blood stream, where it does its dirty work. What I did not realize, until this article, is that in the course of a day the “megakaryocytes”, which are the progenitors of platelets, spill out and replace 20 percent of circulating platelets per day. These new platelets will not be affected by the aspirin and hence blood stickiness may recur transiently. Hence twice a day aspirin might prove more effective, even at very low, better tolerated doses.
As you know, I am keen on getting actual visual evidence of Atherosclerosis, either by coronary artery calcium score or carotid doppler. The primary prevention studies do not use these technologies, so a certain percent of the patients might be getting aspirin, who have absolutely no atherosclerosis and therefore are at very low risk for MI or stroke.They of course,would not benefit . The 200/1500 patients saved by low dose aspirin might therefore be significantly underestimated if patients without any imaging evidence of atherosclerosis were eliminated from the t rial. If patients were included who were at higher risk, i.e. having very high calcium scores on their ultra-fast CT scans, the number of patients saved might be considerably higher in the primary prevention trials.
So, long story short, if you have demonstrated NO atherosclerosis, I would not take aspirin. If there is demonstrated a lot of atherosclerosis I would take 81mg if you weigh under 154 pounds and a full aspirin if you weigh more than 154 pounds. In the latter example, without any hard evidence, I would consider 81mg twice a day. Hey, life is complicated! But, lots of studies are pending to help take us out of our miseries… or perhaps, lead to even more “long-winded” articles.
I just read the first blog on aging… and it was just too much. I will try to be simpler.
There was recently published in the Journal of the American Medical Association an excellent review, and an interesting point of view about the possibility of targeting biologic aspects of ageing not only for prolongation of life, but for wellness.
“Aging as a Biological Target for Prevention and Therapy”, Nir Barzilai, MD; Ana Maria Cuerva, MD, Phd; Steve Austad , PhD JAMA.2018.
The following is an abbreviated summary with occasional digressions.
Let’s start with the generating hypothesis of “geroscience.” Favorable genes, probably some drugs and lifestyle modifications not only prolong life, but to a startling degree prevent disease. The old model is “of course, if you live longer you will have less disease.” But, let’s look at this from a different perspective.
The number and severity of all illnesses go up exponentially with age. So, if one particular disease won’t afflict you another will. If one, therefore, were to successfully cure cancer, let’s say two years would be added to the natural lifespan of the entire population. However, other diseases would soon catch up and people would die anyway from other illnesses.
So, suppose one could target genes to allow you to live decades more. But, if diseases piled up on you while you were living longer, you might think of yourself having made a Faustian deal, and reconsider your decision.
There may, however, be a different reality for those of us who happen to live exceptionally long lives.
Researchers looked at a natural model… humans who made it to 100 years of age. Not only did the centenarians reach this remarkable age, but many throughout their latter decades had NO DISEASES AT ALL, and were remarkably youthful for their ages. In many of the very elderly poor lifestyles didn’t seem to make a difference in their wellness, as well. So, could it be that 100-year-old people are more than a statistically biased group (i.e., since they are the only ones left standing, of course they had no illnesses).
Could it be that the same genes that prolonged aging also prevented cancer, dementia, vascular disease, diabetes, hypertension? WOULD TARGETING GENES FOR LONGEVITY ALONE, ALSO PREVENT ILLNESSES, as might be the case with 100-year old humans.
This line of thought doesn’t preclude the obvious: you get a good ride out of healthy lifestyle changes. But we are talking about the “holy grail” here. What is it about Uncle Louie who reached 100 drinking bourbon, smoking cigars, eating cheese burgers, and who had no diseases, great skin and a legendary sex life?
Ageing is real. We all “lose a step” to use a sports metaphor. Have you ever walked behind a younger person at the same gait and pace, and noticed that the targeted youngster is still putting more and more distance between you? Why does it require herculean efforts to prevent localized fat deposits in unwelcome places? We lose subcutaneous fat and bruise more easily. We get M.I.C. (mild cognitive impairment) and assume it must be Alzheimer’s… it isn’t! We awaken at 4 AM for no particular reason…. Uuuugh!!
Researchers have found specific biologic areas of dysfunction in ageing which can be targeted somewhat with lifestyle modification, and certain drugs. No need to dwell on these but they include decrease in the quality and quantity of stem cells (those bone marrow cells which normally replace dead tissues), inefficient killing and removing of senescence of cells (ageing cells which refuse to die and end up disrupting tissues), increased inflammation which oxidizes and harms healthy cells, abnormalities of protein folding and production, telomere abnormalities (these are the protective ends of chromosomes which prevent deterioration or abnormal fusions with other chromosomes), epigenetic abnormalities (these are important pieces of the genetic code functioning OUTSIDE the cell nucleus, which can be inherited from the female egg and which have many functions). Activation of any one ageing mechanism can affect most of the others.
Animal models using mice prolong life and improve health by over expressing a specific gene and “knocking out” another specific gene. Humans so far seem not quite there, but my guess is we are not far off.
The N.I.H. sponsored a drug intervention trial at three different centers with “heterogeneous” mice approximating a normal mixed population. Twenty-six drugs deemed to be likely candidates were tested. Two in particular were found to prolong life and wellness. Rapamycin and Metformin use together were particularly effective, prolonging life (in human equivalents, 20 years even if initiated in “70” year old equivalent mice). Observational studies in humans using Metformin have demonstrated reduction in the risk of cancer, dementia and total mortality. Clinical trials regarding Metformin use report decrease in diabetes, cardiovascular disease and cognitive decline. Large scale trials using Metformin as an anti-ageing drug in humans are currently underway. Interventions in mice to eliminate senescent cells have also extended life and wellness. Trials are underway using candidate senolytic (destroying ageing cells) drugs in humans.
As for those of us who are resigned to more modest goals of longevity and wellness a brief list comes to mind.
1) A Mediterranean diet avoidance of processed foods and chemical additives. Eat cruciferous vegetables, avoid red meat and excess salt, limit simple sugars, and foods with high glycemic index, consume three to four fish meals a week, use olive oil and eat nuts. Be careful about fish known to having high mercury.
2) Avoiding breathing air with high pollutants and increased micro-particles.
3) Getting enough high-quality sleep.
4) One hundred fifty minutes a week of moderate intensity aerobic exercise.
5) Getting health maintenance checks as indicated for sex and age, including blood pressure check.
6) Getting appropriate vaccinations.
7) Avoidance of toxins to include not more than one glass equivalent of wine per day, cigarettes, mold, inappropriate psychoactive drugs, passive smoke.
8) Skin care to include use of sun block, and avoidance of ticks. Frequent hand washing or use of antibacterial lotions can yield surprising health benefits.
9) Avoid situations conducive to trauma. Buckle up, wear a bike helmet, avoid firearms in your home. If you are prone to falls, design your home for protection and be vigilant with even minor ambulation. Avoid driving while very fatigued.
10) Don’t be afraid to think about stressors and plan to avoid them.
11) Don’t use your doctors as role models!!!
Keep in touch,
Hello out there,
The last two blogs were musings about the importance of bacteria in the gut. While scanning my journals I found two interesting papers. The first is yet another article on unexpected relations of gut bacteria to disease, in this case Lupus, Erythematosus, a disease of autoimmunity, i.e. of the immune system targeting and damaging organs. The second paper was a study possibly identifying a mechanism whereby aerobic exercise improves cognition. I will briefly summarize them, and move on to a more general discussion of EXERCISE. The latter will require more than one session.
James Rosenbaum M.D. and Gregg Silverman M.D. in the New England Journal of Medicine review the importance of the microbiota of the human intestine to “dispose of waste, but also to educate the immune system, regulate levels of neurotransmitters, and synthesize essential nutrients such as vitamin K.” They go into detail about the possible importance of a gram-positive bacterium, Enterococcus Gallinarium as a cause of Lupus. Mouse intestines incubated with Enterococcus Gallinarium become “leaky” allowing unusual substances entry into the blood stream. They were then able to culture the bacterium itself in intestinal lymph nodes and liver. The bacteria then caused the production and release of immune proteins (e.g. interferon-alpha) thought to be contributory to Lupus. The mice contracted Lupus and some of the hallmark serologic findings confirming the disease (anti double-stranded DNA antibodies). Other bacteria which caused intestinal leakage did not cause Lupus. In humans with known Lupus, Enterococcus Gallinarium was found in liver biopsies, but not in human controls. Could antibiotics have a future role in treatment of Lupus? Most importantly, these types of articles are teasers, and it is way, way too early to treat humans based on these findings.
Now… exercise and the brain! Oh really? I stumbled upon an article “Another Reason to Exercise” by Aaron D. Gitler in Science magazine (the magazine of the National Academy of Sciences). About 20% of the magazine is an excellent read on diverse subjects including medicine and the environment. It’s easy to spot the articles which are not comprehensible. They are loaded with derivatives and integrals and other symbols which I have never seen before. Also the review articles are very readable.
Anyway, Gitler reminds us that neurodegenerative disorders are characterized by “the accumulation of insoluble protein aggregates in neurons.” These clearly are at the very least a marker of something having gone terribly wrong and are probably causative in themselves of dysfunction. In Alzheimer’s these tangled bundles of protein are called Tau particles.
Gitler reviewed the research of Fryer et al in the same issue who studied a disease called spinocerebellar ataxia type 1. It’s a rare disease, deadly in children. I know, it’s not Alzheimer’s, so why read on? Hang in there! This disease as well has a bad protein consisting of chains of glutamine residues, produced by a gene gone mad. Exercising mice with this disorder stimulated a salutary protein called Epidermal Growth Factor, which, long story short, via complex series of interactions, influenced the putative gene to secrete less of the glutamine repeats. The exercising mice lived longer and had better memories. So here we have a very nice model of the salutary effect of exercise on brain function. Could a similar process be implicated in the growing evidence that exercise delays decreasing cognition in Alzheimer’s and helps balance in Parkinsonism?
Future blogs will feature more epidemiologic and human trial evidenced regarding exercise and especially what kind and how much should we be doing.
In the last blog, we discussed the emerging field of the microbiome, the collection of genes inhabiting mostly the gut.
So, what does this mean in terms of ideal diet? Continue reading “Your Gut, Your Genes and Your Diet”