Hallmark of Aging 10 - Altered Intercellular Communication

Hallmark of Aging 10 - Altered Intercellular Communication


How did altered intercellular communication make the list? What on earth is that about? To understand it helps to conceptualize us as assemblies of cells. We started as a single-cell organism both at conception, as well as 3 billion years ago. Each of those cells in our now complex, 10 trillion cell organism, still has a certain amount of autonomy, and the need to talk to the other 9.9999 trillion cells. How can the whole organism act in concert unless it is communicating?


There are clear experiments in mice where one can take the serum of old mice, and transfuse it into young mice who will then develop the attributes of aging. Or, take the serum of old mice and dilute it with saline solution, and those mice will appear younger. We can identify packets of messenger RNA called exosomes that are essentially brown bottles thrown out into the void to communicate between cells throughout the body. There are even businesses now isolating exosomes and using them for therapeutic effect.

It's not just exosomes that become degraded. Aging involves deficiencies in neural, neuroendocrine, and hormonal signaling pathways, including the adrenergic, dopaminergic, and insulin/IGF1-based and renin-angiotensin systems, as well as sex hormones loss of reproductive functions. Lots of communication systems are degraded.


The SASP system is a central one. It is intensely involved in tumor suppression. SASP stands for the "senescence-associated secretory phenotype". Aging cells that are at risk of turning into cancer are meant to be arrested in their growth so they don't become cancer. Unfortunately, they don't die either. As zombie cells, they put out all sorts of inflammatory stuff that ends up encouraging cancer cells after all. This gets into the "antagonistic pleiotropy" theory of aging which essentially says that the same gene can have good effects in one situation, and horrible effects in another.

You can sense the intricate interplay of competing forces. There is layer upon layer of competing influences.


www.What will Work for me? The most likely thing to have a tangible benefit are Nrf2 strategies and NO supplementation. Both Nrf2 and NO play a role in the robustness of many pathways. You can boost your Nrf2 with lots of vegetables and PB-125, the supplement from Pathways Bioscience that is the current best of breed for stimulating your Nrf-2 system.


References: Cell, Science Direct, Ann Rev Pathology , Free Rad Biol Med, Wikipedia, Molecular Cell Bio


Pop Quiz

1. Why is intercellular communication so important?                        Answer: As we evolved from single cell to our current 10 trillion cell condo association, we had to develop mechanisms to share the "news" of whatever was happening locally with the whole group. Did you just get invaded my malaria? Got a cancer starting?


2. Can you name a couple of the means of communication?                      Answer: Hormones, nervous system, exosomes, SASP


3. Ok, just what is SASP?                           Answer: "Senescence-association secretory phenotype". A tilt of older cells to become zombie cells that generate lots of inflammatory messages.


4. Can you name one hormone that degrades dramatically with aging other than estrogen or testosterone.   Answer: Sure. NO (nitric oxide) drops by 12% per decade. Can't have healthy blood vessels with no NO. You can buy it and replace it. If you are over 70, just do it.


5. Extra Credit: Can you explain "antagonistic pleiotropy"? Ok: go read about it on Wikipedia.


Hallmark of Aging 9 - Stem Cell Exhaustion

Hallmark of Aging 9 - Stem Cell Exhaustion


Aging is associated with a gradual degradation of stem cells to replace the worn-out cells in any particular organ. Each organ appears to have its own source of stem cells and its mechanisms and means of eliciting their revival. Injury is a frequent cause of stem cell regeneration demand. Because it is the site of frequent injury, the skin has multiple cells that can be recruited to become stem cells. Muscles, on the other hand, appear to have a predetermined hierarchy of stem cell regeneration. Most organs have a much slower regeneration cycle as they don't suffer the frequent injury cycle of the skin. Tissue injury results in de-differentiation of many cell types. By way of example, in the intestine, brain, and lung, injury induces de-differentiation of non-stem cells, which proceed to reactivate normally silent embryonic transcription programs. One doesn't think of the lung being injured until you imagine sitting over an open fire trying to cook meat while hyenas prowl just beyond the shadows. You breathe in all that smoke and injure your lungs, but you keep the hyenas at bay with the fire.


By reacting to injury you have also acquired the plasticity needed for tissue repair. Your mature cells have "regressed" and become less mature, differentiating back into stem cells. Four key enzyme systems control all this: OCT4, SOX2, KLF4, and MYC (OSKM). You have heard of this as recent news reports talk about taking ordinary skin cells and using them to create stem cells, even eggs for starting an organism from scratch.


This differentiation back to a more primitive cell type doesn't erase the epigenetic markers or the Hayflick clock completely, suggesting that differentiation and rejuvenation are linked. But much does not re-establish of the erased aging-associated changes and therefore resets the epigenome and transcriptome to a younger state. Something about injury establishes a younger state. Hmm, is that the benefit of weight-bearing exercise? Slight injury causing younger regeneration.


The problem with aging is that this all just plain slows down. You can only bench-press your way out of trouble for so long.


www.What will Work for me? I look at the age spots on my hands and forearms and consider all the sun damage my skin has endured. I'm not in the market for fertility treatments, but the idea of setting back the epigenetic clock is intriguing. I'm glad there are lots of researchers all over the world working on this.


References:Cell, Development, Cell Stem Cell, Cell, Technology Networks, Science,


Pop Quiz


1. What is stem cell exhaustion? Answer: The inexorable winding down of the ability to repair after injury.


2. Where can you see this process playing out on your own body? Answer: How long does it take for the bruise on your arm to fade, the cut on your arm to heal?


3. Is there some unexpected benefits to exploring tissue repair? Answer: Yes, we now understand how to turn back the differentiation of mature cells to capture the "pluripotential" of stem cells.


4. How far back? Answer: All the way to the original stem cell, the egg.


5. Are researchers sharing everything they know on this topic? Answer: Are you kidding? This is big-buck territory because of the fertility industry. To discover and profit from findings is a high bar to overcome.

Hallmark of Aging 8 - Cellular Senescence

Hallmarks of Aging 8 - Cellular Senescence


We are up to eight Hallmarks! Two to go! Cellular senescence caught my curiosity. The fact that there is now an international organization dedicated to studying cellular senescence speaks to the seriousness that people are now giving this topic. Every tissue makes senescent cells, at wildly different rates. "Endothelial" cells, the lining of organs and arteries, fibroblasts, what holds tissues together, and immune cells are the most common sources of senescent cells. Brain and heart tissue hardly have any senescent cells at all, unless you examine our politicians.

The best argument for the recognition of senescent cells' damaging role is the prolongation of life and wellness in multiple experimental models of aged mice, by the elimination of those senescent cells by pharmacological means.


Healthy, functional cells are called "quiescent" meaning they are alert, alive, and ready to go when needed. The best analogy is a squadron of soldiers in parade uniform, at ease and all lined up in parade formation. They are ready to go.


Now, imagine those same soldiers back in the barracks playing poker in their underwear and having their third beer. They are inviting you to join their poker game. They aren't doing their assigned function. Senescent cells are like zombie cells, infecting their neighbors and spreading their own maladaptions.

Therein is the problem. Senescent cells damage the cells around them with increasing levels of messaging that nudges the cells to act older. What do you mean by "act older"? Well, we aren't so sure, just yet. We believe the complex portfolio of mRNA molecules, coding for hundreds of different seemingly unrelated chemicals and compounds all have a complementary influence on aging. We see that in the use of exosomes from older mice injected into younger mice. Harvest their exosomes (tiny packets of 100-300 mRNA) molecules circulating in the blood of all animals, including humans) that are the organism's method of coordinating the whole organism to similar behavior. Harvest those exosomes and inject them into younger mice. Presto, chango. They become much older. Reverse it and they become much younger. When it comes to me, please make sure you get the right vial.


In case you thought the topic was that simple, consider just one quote about one feature of senescence. "Another important event during senescence is the depletion of lamin B1 from the nuclear envelope. This results in the loss of lamin-associated heterochromatin and de novo formation of heterochromatin rich in H3K9me3, a process that can be visualized as HP1α foci or senescence-associated heterochromatin foci (SAHFs)." It's not simple and parsing out the details is a challenge for the ages. But a good start is naming it, and beginning to devise means of studying it.


There is no single marker of senescence yet identified but there are some features when taken together are enough make a working list: (1) lysosomal expansion, detectable by SABG; (2) upregulation of CDK inhibitors, particularly p16 and/or p21; (3) loss of LMNB1 from the nuclear envelope; (4) loss of the chromatin component HMGB1 from the nucleus and its extracellular release as an alarmin; (5) heterochromatic foci, visualized as HP1γ nuclear foci or SAHFs; (6) high levels of ROS; (7) exacerbated DNA damage, visualized as γH2AX nuclear foci; and (8) high levels of SASP factors, notably IL-6, TGF-β, PAI1, and others.

My eyes glazed over before I got to 7. This is hard-core cellular biology.


www.What will Work for me? There continues to be interest in some sort of senescent strategy for our individual lives. The taking of Sirolimus, an analog of Rapamycin (an antibiotic produced by an actinomycete bacteria found at the foot of one of the monoliths on Rapa Nui, (Easter Island)) is popular in the high-end range of anti-aging efforts. It's probably just as beneficial to have you include some sort of ketosis strategy and growth hormone inducement by peptides. Those are the three things that I do. I'm still alive.


References: Cell, Cell,


Pop Quiz


1. What is cellular senescence?                        Answer: The slow accumulation of damage from various sources.


2. What is the problem with senescent cells?                        Answer: They are zombies and don't do their function properly. Moreover, they recruit neighbors to be just as dysfunctional.


3. Do we have good proof of the concept?                        Answer: No, the research is pretty nuanced and our best crack at it is the prolongation of life induced in aged mice with various senescent cell-killing strategies.


4. Are there other strategies that may help that shift?                       Answer: Yes, growth hormone, exercise, fasting, and ketosis all play a part.


5. Are there clear markers of senescent cells?                         Answer: No. It appears to be a subtle continuum. All cells start as quiescent. Somewhere along the line they fall off the cliff and get reprocessed - "autophagy". I suspect that subtle degradation has to include loss of plasmalogens in the membranes. I could find no mention of that anywhere, but it is the only way one can square the evidence of plasmalogen functionality and the philosophical construct of senescence. If I were a starting out PhD student, this would be my consideration for a thesis.

 
Hallmark of Aging 7 - Mitochondrial Dysfumction

Hallmark of Aging 7, Mitochondrial Dysfunction


You are 10% mitochondria by weight. They are your powerhouses inside each cell where they turn the energy of carbohydrates and fats into carbon dioxide and water. Like a carefully tuned engine they work well when the energized electrons have some place to go...like exercise using up the energy molecule ATP (Tri-phosphate) into ADP (Di-phosphate) that then returns to the mitochondria to be remade into ATP, 10,000 times a day. On a good day, 1-2% of electrons escape and there are layers of protection to capture those errant, loose electrons and neutralize them.


 The first line of defense are the enzymes superoxide dismutase and catalase, that basically capture the electron and plug in into a water molecule to make hydrogen peroxide, or the Hydroxyl ion. But most importantly, they get the loose electrons out of the cell, saving the cell from death. In the extracellular space, the second line of defense is glutathione. That's what glutathione does, it captures peroxide and neutralizes it. Virtually every chronic brain disease has low glutathione because of the ongoing oxidative stress.


In the situation of overwhelming oxidative stress (COVID-19 infection, anesthesia, 4 scoops of ice cream, ) some excessive peroxide makes it as far as the cell wall of the cells where it runs into plasmalogens. Plasmalogens are on the outside surface of every cell and function as the antioxidant of first resort. They also allow embedded proteins to function with blinding speed because of their ability to shapeshift and their liquidity. They snuff out peroxide, but they sacrifice themselves. The membrane loses one molecule at a time. The chemical malondialdehyde is the result of that chemical reaction, peroxide meeting plasmalogen. Virtually every brain disease has elevated malondialdehyde.


Depletion of plasmalogens is the best predictor of how long you live. Period. And it's not just extracellular plasmalogens that are being damaged by oxidative stress. Inside every cell, the mitochondria itself has some 50% of its own internal lipid membranes are made of plasmalogens. They get damaged too.


Here's the rub. Every article I read about mitochondria degrading and having some form of dysfunction dances around the question, "Why?". We can see it happening. We can see the effects of damaged mitochondria. We can try to reconstitute mitochondria, but what are we really doing? We are documenting and observing mitochondria becoming inefficient and losing increasing amounts of electrons, creating a gyre of increasing oxidative stress, depleting their own plasmalogen supply, but also every cell in the body's supply. But no one has gone the next step to study the repair of mitochondria with plasmalogens.


We know mitochondria have a huge proportion of their membranes made up of plasmalogens. On the order of 50% by best recent research. We know every detail of the electron transport chain in the mitochondria that passes on those highly charged electrons from complex to complex, but no one has ever turned and looked at the membranes that are supporting those electron transport chain proteins. If they are losing their plasmalogens, their supporting membranes are becoming stiffer and more rigid. The embedded proteins can't function quite as well. It's just been the last year or two that review articles about membrane function and mitochondrial decline being linked. That's the key to follow.


My hypothesis is exactly that. We die when our plasmalogens run out. Our mitochondria can't keep making energy and the gyre of increasing release of oxygen radicals destroys cells all over the body. Curtains.


www.What will Work for me? There has to be some link between the eerie predictability of longer life with higher plasmalogens. That means shorter life with lower plasmalogens. When our mitochondria stop working, everything collapses. With the advent of plasmalogen supplementation, we have a new dawn of possibilities. I'm eager to see more data. For now, all I see is description of the trouble we are in when our mitochondria go south. We need to learn how to test their resilience and function better. 


Urolithin, labeled Mitopure, is the first product on the market directed at mitochondrial repair. Urolithin was found in pomegranates. I love pomegranates, for the 3-week season, they are available. This is where methylene blue, (yes, the party blue dye you put in the drinks and everyone swimming in the pool gives a clue if they pee in the pool) kicks in. It also bypasses the block that the spike protein of COVID creates in mitochondria. Eventually, we are going to have a better formula on how to get around that aging thing. Right now, our best bet is Prodrome Neuro and Glia. Those two supplements help rebuild your plasmalogen pool, wherever it may be.


References: Cell, MDPI Antioxidants, Frontiers Cell Development Bio.Curr Opin Cell Biol, ,


Pop Quiz


1. What role do plasmalogens play in regard to calming oxidative stress manifesting as elevated hydrogen peroxide?                          Answer: They are the antioxidant of first resort.


2. What proportion of mitochondrial membranes are made up of plasmalogen lipids?                          Answer; On the order of 50%


3. What makes them so valuable in mitochondria?                                Answer: They are the most fluid of membrane lipids and also have the capacity to shape shift. That facilitates the actions of embedded proteins that frequently have to change shape, 100s of times per second.


4. What does urolithin do?                      Answer. It is the first supplement on the market to address biogenesis of revived mitochondria.


5. Where was urolithin first found?                            Answer: Pomegranates.


Hallmark of Aging 6 Deregulated Nutrient Sensing

Hallmark of Aging 6 Deregulated Nutrient-Sensing


This is one of the most preserved genes in all living cells. There is a choice! Lots of nutrients and you can grow, blossom, reproduce and die, or you can have less nutrients and hunker down and live longer. Can't have both. You choose.


Valter Longo described this in single cell yeast and in fruit flies, earthworms, mice and humans. All the way up the evolutionary ladder. Nutrient sensing is key to the balancing of that teeter-totter.

 

The mechanistic target of rapamycin (MTOR) complex-1 (MTORC1) responds to nutrients, including glucose and amino acids to modulate the activity of numerous proteins including transcription factors. The MTOR network is a central regulator of cellular activity, including autophagy, mRNA and ribosome biogenesis, protein synthesis, glucose, nucleotide and lipid metabolism, mitochondrial biogenesis, and proteasomal activity. Sensing nutrients is key to all those processes, and mTOR is its means of control.


Diverse hormones like insulin, IGF-1 all play a role in the network feeding back into mTOR. When nutrients are abundant, mTOR turns on "building up and reproducing successfully" and when nutrients are absent or restricted, the reverse occurs: hunker down and slow down metabolism so that you live longer, hoping to outlast the famine. (Every dieter knows this. A prior diet of 800 calories a day fails when one returns to just 1400 calories because their body has gotten lean and mean and turned on nutrient conservation, living longer).


Again, a fascinating rabbit hole if you want to learn what PI3K-AKT and the Ras-MEK-ERK pathways are, or what FOXO3 transcription factors do. But it all comes back to that nuanced teeter-totter of nutrient sensing that falls apart and becomes dysfunctional when we get past 40. Then, we start getting older, and fatter.


Fasting and dietary restriction inhibit MTORC1 and EP300; activate AMPK, SIRT1, and SIRT3. There you have it all in one sentence, non of which you understood. It's complex but again, there are discrete pods of researchers delving into it.. This is, in fact, what Longo advocates for, 5 days of 800 calories at least 4 times a year, better if more often. And the peptide advocates are using rapamycin analogs like Sirulimus that can be prescribed. Longo's fast mimicking diet has been proven to double the effectiveness of chemo therapy and to add 15 years to health span for those who practice it regularly. It induces ketosis.


www.What will Work for me. Ketosis is the sign that you are in nutrient shortage and are beginning to turn on internal autophagy (recycling old pieces to turn into energy) and activating anti-aging mechanisms. There is now some evidence that taking ketones as a daily supplement provides the same benefit. This is a fun little body hack. You can buy ketone esters and ketone drinks now and get into ketosis by just popping the top of a can. The very flavorful new product called Kenetik (www.drinkkenetik.com) dose just that, and every lecturer and teacher of longevity strategies seems to have a bottle of Kinetic at their podium as they speak. At $ 5 a can, it's a bit pricey, but no worse than a Starbucks stop, and likely better for you. I've ordered a six-pack, and son of a gun, it gives a nice boost. Different than coffee.


References: Cell, Science, Ketones, The Fourth Fuel,


Pop Quiz


1. Why is nutrient sensing so important?                              Answer: Organisms have to reproduce and good nutrition helps that happen, but organisms also have to be ready to survive famine. It's a yin and a yang. Live longer, hungry?

2. What are ketones?                               Answer: They are the 4 carbon pieces chopped off of fat molecules that are typically 16 carbons long. So you get four of them out of one fat molecule.


3. How long does it take you to start being in ketosis (making ketones)?                                  Answer: You can only store 1500 calories of carbs. Hence, 12 hours of not eating and you start flipping from running on glucose to running on fat and your blood ketone level will be 0.1. If you do Longo's diet for 5 days (800 calories a day, vegan, <8% protein), by day 5 your ketone level will build each day and be at 3.5-4.0 by day 5. That's full ketosis.


4. How can you use fasting to your benefit?                                   Answer: Longo has demonstrated that done at least 4 times a year results in 15 years of extra health span. This is the most powerful modality we know for anti-aging. You are toggling your nutrient sensing system back into function. But a little less severe will work to. Skip breakfast and concentrate your calories into 8 hours. You get 4 hours of daily ketosis.


5. Is there a book I can read about Ketones.?                               Answer:YES! Ketones, the Fourth Fuel by Travis Christofferson.


Hallmark of Aging 5 - Decreased Autophagy

Hallmark of Aging 5 - Disabled MacroAutophagy


Here is another mouthful to learn about. MacroAutophagy, or just autophagy for short. It's how we get rid of the big stuff. In everyday life, your regular garbage goes out in the trash can. If it's too big, you call the company and ask for the big truck to take your ....old freezer, washing machine, or whatever, away.

In your cell, the big garbage truce is called an autophagosome. It is a separate little entity in the cell, designed to surround or envelop old, used-up parts of the cell that need recycling. That autophagosome then fuses with a second entity called a lysosome that is basically a package of digestive enzymes you wouldn't want running loose inside the cell. Whatever is in there, it gets chopped up and all the amino acids, fats, and sugars come out as their basic selves, ready for building something new.

Old mitochondria, broken proteins (often misfolded), bits of misplaced DNA or RNA, and even bacteria and viruses are all chopped up and reprocessed. At least that's how it's meant to work.

Then there is the city dump you can take stuff to. In your cell we call that an exosphere, which is basically a membrane containing the junk to be reprocessed that is packaged up, spit out of the cell into the blood, and destined to be chewed up and digested by white cells called macrophages that envelope it, take it in and digest it. They do it the same way. They have packages of enzymes that fuse with their internal package of "garbage". All neat and tidy.

All these disposal mechanisms give the cell leeway to clean itself up. If one pathway doesn't do it, the next can pick it up. Until it doesn't. There is clear evidence that decreased macroautophagy is a problem. In multiple experimental models, animals with good macroautophagy live longer.

Reduction of autophagic flux may participate in the accumulation of protein aggregates and dysfunctional organelles, reduced elimination of pathogens, and enhanced inflammation because autophagy eliminates proteins involved in the inflammasome and their upstream triggers.


You begin to realize there is a whole universe of research going on into autophagy with several journals dedicated to its discovery. We need it to keep generating fuel when we go through famine, as our bodies selectively break down cellular elements to keep us fed. Mice with knock-out autophagy genes die of hypoglycemia because they can't generate glucose. The list and nuances merit a whole afternoon of reading if you want a rabbit hole to go down.


On the other hand, when garbage accumulates, old, dysfunctional organelles like mitochondria, instigate inflammation. Just like keeping compost in your kitchen starts making a smell and cockroaches move in, the breakdown of autophagy leads to cellular inflammation and eventual early demise.

www.What will Work for me? This gives another reason for some sort of fasting behavior. It sharpens up all your internal tools of autophagy. And one more time, we find an interplay with the Nrf-2 antioxidant controlling system and autophagy. There is a cross-talk and shared enzymes between the two. I can take the supplement PB-125 from Pathways Bioscience because the food extracts in PB-125 stimulate the Nrf-2 system, under which autophagy is at least partially controlled. I pay my village taxes to have my garbage taken each week. I need to restrict calories in some fashion to do the same internally.


References: Cell, Cell, Autophagy, Frontiers Cell Devel. Biol.,


Pop Quiz


1. What is autophagy?                                    Answer: The internal garbage disposal system inside each cell.


2. What is its function?                                Answer: Several key issues. Getting rid of broken intracellular proteins, DNA, and organelles that will induce inflammation is one point. But having the ability to hunker down and reprocess parts of the cell to make fuel in time of lean nutrients is also key.


3. If you knock out an autophagy-controlling gene in mice, what happens if they are deprived of food and go through a spell of starvation?                                 Answer: They die of hypoglycemia.


4. What is the system controlling autophagy?                              Answer: We may not have the whole picture but the Nrf-2 system certainly has overlaps. It is the central controlling system for all inflammation.


5. Is there any one thing I can do to induce better autophagy?                           Answer: Yes, intermittent fasting, forcing your cells to be a bit hungry, induces the internal repurposing function and keeps the enzymes tuned/sharpened. Besides taking PB-125 from Pathways Bioscience.


Hallmark of Aging 4 Proteostasis

Hallmark of Aging 4, Proteostasis


Whew, I bet that pulls you up short. Can you pronounce that? Do you have a clue why it would be on the list? Or what it even means? Proteostasis. It all starts with your "proteome". That's the universe of all your proteins. Just like the genome is the measurement and stage of all your genes and the metabolome is the whole sum of all your metabolic products made by your genes, the proteome is the universe of your proteins.


Proteins are delicate little creatures. They have to be folded into just the right shape. It can take two or three chains of amino acids to make the final protein. They get tricked out with all sorts of extra sugar molecules and an atom of zinc, or selenium, or cobalt, or whatnot. They have lots of little additives pasted and glued in place. Then, after all that, we ask them to do impossible things incredibly quickly. We take that all for granted. Many enzymes take various compounds and break them into pieces, or add a piece on.

This is not a trivial issue. The accumulation of beta-amyloid occurs in Alzheimer's because of the inappropriate activation of wrong proteins. ALS is associated with mutations in proteins that render them intrinsically prone to misfolding and aggregation. That saturates the mechanisms of protein repair, removal, and turnover that are required for maintenance of the healthy state.

Then there is the whole system of properly recycling old proteins that need to be broken down and their products recaptured. The field of protein maintenance is actually quite complex with whole fields of study in all the details.


Finally, there is the Nrt -2 system (nuclear factor (erythroid-derived 2)-like 2) and its effect on proteostasis. The Nrf-2 system was thought to be the master regulator of inflammation but it's turning out to be much more. It is a a key component of the transduction machinery (mobilizing the right DNA in order to activate a process) to maintain proteostasis. In a sense, the Nrf-2 system is a hub that compiles emergency signals derived from misfolded protein accumulation in order to build a coordinated and durable transcriptional response. (Did you get that?). Whew.


www.What will Work for me? I can do something about the Nrf-2 system. We've talked about that before. The Mediterranean diet and the Okinawa diet explained because the vegetables and green foods commonly eaten by them induce Nrf-2 activation. Our Nrf-2 system declines as we age and doing something about it is now possible. The first introduction to that market is the product from Pathways Bioscience called PB-125 that you have to buy directly from them. It's not on Amazon. Buy it. Take one a day. It's just the spice rosemare with luteolin and ashwaghanda. Those three plant foods are synergistic in their Nrf effect. Your proteins will appreciate it.


References: Cell , Redox Biol,


Pop Quiz


1. Why is proteostasis so complicated?                                   Answer: Because every process of life is run by proteins which have thousands of different forms, shapes, means of being folded, extra components, and then exposure of toxins, poisons, oxidation, not to mention recycling and disposal


2. Just what does proteostasis mean?                            Answer: maintaining the state of proper function of all your proteins. That's life itself .


3. How does the Nrf-2 system interact with proteostasis?                                 Answer: Ah! It appears to be the master controller of turning on the right genes to keep your proteome in tiptop shape.

 

4. How can I fix that?                                      Answer: Here is my pitch for PB-125. I don't have any financial relationship with them. I just take it myself.


5. Any other suggestions on how to maintain my proteome?                               Answer: It's a massive topic with huge research going on. Taking plasmalogens allows your membranes to function better. We're going to see more research on that.


Epigenetic Alterations - Hallmark of Aging 3

Epigenetic Alterations, Hallmark of Aging 3


Can you define the "epigenome"? It's not your DNA. It's not the genes tucked into your mitochondria. It's not even DNA. It's the markers on the outside surface of your chromosomes that curiously pass on some of their information to subsequent generations.

For example, two famous famines, in northern Sweden in early 1900 and in Holland during World War II, the offspring of those who suffered through those starvation times can be shown to still have metabolic abnormalities into the third generation. Another example, emotions that pass on in families reflecting generational trauma or even just cultural trends have some of their roots in epigenetic measures. Is that what drives the persistence of racism and its painful recurrent generational trauma?


Another example is likely the means by which all animals pass on their advice to their offspring. Fear of predators and safety of groups appears to be ingrown. Yet deer, living in safe places (our suburbs) become so accommodated to humans they are brazen in their nibbling on our flowers. The elk of Estes Park in Colorado are famous for their virtual occupation of the town. They have no fear. Town is safe. Their DNA has not changed. What passed on their behavior? Likely epigenetic changes.


Your epigenome is the markers on the outside of your DNA that instructs your body when to hold 'em and when to fold 'em. When to activate DNA and when to shut it down. There are some 20,000,000 of them on your chromosomes in complex web. You can attach a one-carbon signal (methyl group) or a two-carbon signal (ethyl group) to DNA or to the histone proteins. Each has separate signals.

Then there are the Sirtuin proteins tasked with caring for your DNA. Humans have 7 of them. Single-celled primitive life forms only have one sirtuin. The sirtuins are the groomers and repair specialists of your epigenetic system. They run on the NAD energy system instead of the ATP system. It's much less efficient and much more primitive, suggesting that sirtuins have been central to cells duplicating themselves since time immemorial. NAD declines with aging.


Hence, David Sinclair in his awesome book, Lifespan, argues that you need to take metformin, the diabetes drug at a 25% of effect (500-800 mg a day) to stimulate the production of more sirtuins, and NAD (otherwise known as niacin or Vitamin B3) in order to power them. This is all in the service of caring for your epigenome.

The frontier of cancer care now is all about measuring the detectable alterations in your epigenome that lead to cancer risk (marked reduction in markers). There are even companies offering cancer screening with high rates of specificity for some cancers. It's very complex because the 20 million markers aren't written in plain English, but pattern recognition is beginning to take hold.

Epigenetic modification mechanisms are still being discovered. There are all sorts of messenger RNA including circular mRNA and micro RNA particles that aren't coding for proteins that have epigenetic actions. If you want a really deep rabbit hole, type in retrotransposons and aging. (DNA segments that can get up and move their place in chromosomes and wreak havoc.). They play a role in cellular senescence, a cardinal sign of epigenetic exhaustion.


www.What will Work for me. I have used epigenetic markers to measure my biological age compared to my calendar age. I have used epigenetic markers in my clients to look for cancers, with satisfying responses. I'm taking metformin and NAD to care for my epigenome. I'm stymied about the complexity of it all but I do know that simply allowing my body to get into ketosis helps most of this. Prolonged starvation is such a drag, but a bit of induced starvation (skipping breakfast) or manufactured starvation (energetic exercise) likely accomplish the same thing, without the death part.


References: Cell, Oxford Handbook of Emotional Dysregulation, Overkalix Study-Wikipedia, American Jr Biolog Anthropology, Lifespan by Sinclair,


Pop Quiz


1. What is your epigenome?                     Answer: The markers on your chromosomes that indicate when to activate and when to silence genes.


2. Do you actually pass those genes on to your kids?                   Answer: Yes, to some degree. How, we don't quite know yet.

3. What are those markers?                       Answer: simple one and two carbon compounds, methyl groups and ethyl groups.


4. What are the proteins tasked with caring for your epigenome?                   Answer: The sirtuin family, stimulate by metformin and powered by NAD.


5. Can you name one dramatic effect of metformin and NAD?                        Answer: No fair, this answer takes reading Sinclair's whole book. But here it is. Recently menopausal women may get their period back when starting metformin and NAD. Some may not think of that as a major leap forward.


Telomere Attrition Hallmark of Aging 2

Telomere Attrition, Hallmark of Aging 2


Do you know what a telomere is? Yes, it's the cap or end of the chromosome that doesn't code for any protein. The enzyme that duplicates DNA has to have a fixed number of base pairs inside the protein to do its work of copying the DNA. When it gets to the end of the chromosome, it has those base pairs inside it but unable to be reached. Those final base pairs get lopped off. The chromosome is a tiny bit shorter. That is a rate-limiting step on how many times that cell can duplicate.


This isn't the same phenomenon as "genomic instability", Hallmark #1 because of the action and function of an enzyme called telomerase. It can lengthen the telomere and there is research in mice and humans on how to do just that. In some cancers, the activity of telomerase actually helps lengthen lifespan and kill off the cancer faster. That makes telomere lengthening and shortening a separate phenomenon. The inexorable march of that shortening explains the observed phenomenon called the Hayflick Limit that predicts how many times our chromosomes can duplicate, and therefore how long we can live.


Yes, you can lengthen your telomeres. There is a 6-protein complex called shelterin that makes the repetitive sequence of base pairs TTAGGG. That sequence is what is repeated in telomeres. When there are enough of those sequences, shelterin can attach and in just the right circumstances, stimulate telomerase to make longer telomeres.


One clinical example is a study in thejournal Lancet on 25 men with prostate cancer compared to 25 controls. The prostate cancer group was put on a plant-based diet, nudged into more exercise, provided with extra social support, and given stress management exercises. In just three months, their telomeres were longer compared to the controls whose telomeres had lengthened.


The NHANES study, the largest, ongoing study of adults in America reviewed every 10 years with comprehensive dietary analysis, shows that for every 10 grams of extra fiber per 1000 calories, your telomeres will be 83 base pairs longer. That translates into 4-5 years extra lifespan.


We can now quantify telomere length in the research lab. There are also companies that will measure your telomere length for a fee. Just type in Telomere measuring and you will find a raft of companies providing the service. Consider pledging to yourself extra exercise and more fiber and see how you do. Add some meditation and stress management to the mix and you will replicate some of the process that has been done in research labs elsewhere.


www.What will Work for me? I measured my biological age last year and did a test on myself. I reduced my biological age by some 9 years by taking Tartary Buckwheat and metformin. This is something that is within your reach to do too. It's a fascinating rabbit hole to go down and I'm mesmerized by the concept. One more time, exploring the Hallmarks of Aging reinforces the lifestyle methods you can follow that can be measured and documented with tests that are now coming online. Those tests aren't to be found at your regular family doctor who is examining you for the presence of disease. If you have to get a tattoo this week, consider making it TTAGGG, just to remind you to have the salad instead of the pizza.


References: Cell , Cell Metabolism, Nature Review, Nutrients, Wikipedia, Lancet


Pop Quiz


1. What is a telomere?                            Answer: Aw, come on. That's a softball. It's the "Nonsense DNA" on the end of your chromosomes that gets shortened with each duplication of your chromosomes.


2. Is there a name for the result of all that shortening?                           Answer: Yes, the Hayflick Limit.


3. Can I lengthen my telomeres?                      Answer: Yes.


4. Name one strategy you can add to your lifestyle that will help you lengthen your telomeres.              Answer: Exercise, fiber, stress management, plant-based diet, social support.


5. Can I escape the Grim Reaper doing all those things?                  Answer: Well, maybe 5 years extra. Adding plasmalogen supplementation may add more.


Hallmarks of Aging 1 Genomic Instability

Genomic Instability - Hallmark of Aging #1


"Please, please write your newsletter about the Hallmarks.....I want to know," asked one of my clients. I couldn't rattle them off by memory, so here is one of them. Genomic Instability is listed as the first Hallmark. This idea of Hallmarks of Aging has been proposed in 2023 and caused a great stir in the research world. The twelve initially proposed hallmarks are genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. Sounds like jargon. I want to turn it into understandable English.


Each cell in our body has enough DNA to reach about 6 feet in length. The process of duplication of cells, activation, and deactivation of genes, and reproduction, all in an environment of toxins and radiation that breaks DNA means a prodigious amount of DNA repair must occur. Any given cell has to decide as to where their energy is going to be allocated: repairing DNA or living longer and reproducing. Sex always wins. We have to reproduce, which means our DNA has to get old.


With all the means of damaging DNA around, our DNA ends up with point mutations, deletions, translocations, telomere shortening, single- and double-strand breaks, chromosomal rearrangements, defects in nuclear architecture, and gene disruption caused by the integration of viruses. I didn't even mention transposons. (What are transposons? That's the process of taking a whole segment of DNA and inserting it into another organism. CRISPR is basically transposon methodology turned into medical intervention)


Once you have taken care of nuclear DNA, you discover there is a whole universe of DNA pieces floating around in the cell water, the cytosol. That cytosolic DNA is not meant to be there, and it arouses an innate immune response called "sterile inflammation". That is inflammation set off without an invading bacteria.


We are meant to have repair mechanisms. Our sirtuin proteins are just that, the caretakers of our epigenome (the markers on the surface of our chromosomes.). The very, very first cell had to have several key elements. DNA that could duplicate itself, some means of assembling a membrane, some means of generating energy, and some means of repairing broken DNA. Every order of living beings on planet earth has sirtuin proteins. Fasting turns them on. Metformin turns them on. Metformin activates SIRT 1 (the first of 7 sirtuin proteins in humans) that essentially mimics the same pathways as calorie deprivation. SIRT1 is energized by NAD or niacin.


Hence, the combination of metformin and niacin helps everyone live a little longer. Provided they get enough NAD. NAD (otherwise known as Vitamin B3 or Niacin) declines with aging. NAD+ declines with age largely due to the activation of CD38, an enzyme activated by the inflammation produced by senescent cells – cells that no longer grow or replicate. In a feed-forward cycle, the decline of NAD+ by CD38 induces the spread of more senescent cells and inflammation.


Genomic instability is a deep rabbit hole with many publications and journals covering it. It's a great way to spend a rainy afternoon if you don't like golf.


www.What will Work for me. I'm on metformin and niacin. I do my intermittent fasting too. I'm surprised to learn that one of the Hallmarks of Aging fits so well with David Sinclair's concept of everyone being one metformin and niacin. David Sinclair has started a large placebo controlled trial to work this out in scientific rigor. It's going to take 7-8 more years to get results. Now I want to know the other Hallmarks and see how we can incorporate their physiology to our advantage. Stay tuned.


References: Cell, Curr Genomics, Cell, NAD.com,


Pop Quiz


1. What are the Hallmarks of Aging?                            Answer: So far 12 interconnected processes that demonstrate degredation with aging. If we can understand how they fall apart, we gain insight into how to address them.


2. What are the problems with Genomic Instability?                                 Answer. Duplicating DNA and turning genes on and off takes a many stepped process that is intricate to the extreme. Any mistake breaks DNA that has to be repaired. That doesn't always go well. Then there are viruses that insert their DNA into ours. Then there are chomosomes that swap genes back and forth with each other. We are still discovering all the ways it goes wrong.


3. What is "sterile inflammation"?                        Answer: Our DNA is kept in the nucleus of the cell in a tightly controlled place. When a piece of DNA ends up outside the nucleus in the cellular water, it elicits an immune response. We get inflammation without bacterial invasion...so called sterile inflammation.


4. What are the proteins tasked with caring for our epigenome, the markers on the outside of our chromosomes?                         Answer: Sirtuins. The most ancient and preserved of all proteins.


5. What does metformin do that helps aging?                             Answer: Turns on the production of sirtuins, just like fasting does. (Nice to find a way to get around that obnoxious fast.)

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