On the subject of immortality. The field has stalled again, so I have decided to go public. Hang on, I have little choice as I am out of the loop, the Illuminati's offer to reveal the secret to immorality comes with one condition, “we would have to kill you” (Hmm, accent sounded Japanese). This guide is in summary form. With inquiry arise charlatans and frauds, be it Harvard grape juice or another miracle nootropic, no human studies and likely not add a single day to life instead take several away. The answer to the French paradox is not “150,000,000 glasses of wine (sic)”, resveratrol is destroyed by sulphuric acid in the stomach and not bioavailable, like most vitamins and supplements are rejected during digestion and never pass into the bloodstream with prolonged use not advised due to digestive system damage. A recent human trial of nicotinamide riboside (NR) concluded “no clinical benefit to supplementation” and many supplements do not contain the purported active ingredient, wrinkle creams have always been ineffective, except for Retinol. Every so often a new fad pill comes onto the scene promising age reversal that cannot be ignored like CoQ10, PQQ, Omega 3 or a fruit with a fancy name from an exotic place, but they soon fade away in preference for a newer fad. Much in this field is not patentable so there is no interest even if it solves pathology. Many physicians have become no more than pill pushers in return for kickbacks from drug companies and the “eat this”, “eat that” crowd have amassed a huge eating list, fasting is in and “good for you, bad for you” is so last year. The environment critically and increasingly poisonous, constant vehicle exhaust, noxious gas, polluted air, water and food with all sorts of heavy metals, chemicals, toxins, pesticides and more, pills cannot be a remedy against bad living conditions. Review history, no prizes for guessing where the autism is coming from. Ageing is bigger than one minor detail, drug, supplement. We all want it to be real, so let's make it real…
What is getting old like? People look old, and feel old, declining energy levels and no means of restoring energy levels, you cannot eat your way out of it. An optimal night sleep seems to reset energy levels but nowhere near a young person. Exercising effectively is physically impossible. Sluggish, tired, slow, limited, aches and pains, differing in ability and appearance compared to a young person. I saw a child doing full flip scissor kicks and land on his body repeatedly and thought if I attempted the same, let alone unable to exert enough energy to flip my entire body 270°, but landing like that would certainly incur a 3-week recovery time injury. Take an end of life boxer that steps into the ring with a rising force and is beaten badly, yet that same boxer was unbeatable in his younger years. See Hallmarks of Ageing, Aging The Biology of Senescence. Ageing has historical, artistic narratives such as The Fountain of Youth, a painting by Lucas Cranach the Elder (1546) and depicted in the movie cocoon where evil elderly humans drain the rejuvenating pool and kill the ancient cocooned aliens the pool was made to rejuvenate. Right: US 7 Pillars of Ageing vs. Europe Pillars of Ageing. Theories Of Ageing with two predominant theories. Programmed theories, ageing follows a biological timetable, like puberty. This regulation depends on changes in gene expression that affect the systems responsible for maintenance, repair and defence responses. Damage theories emphasize environmental assaults to living organisms that induce cumulative damage at various levels and eventually critical damage such as obesity, no exercise and radiation damage the body. Most people do not want to die but no one lives forever, nature's 100% perfect strike rate. There is always an exception. No exceptions!
Ah, exception, in nature there is an animal that has immortality. Turritopsis dohrnii, the immortal jellyfish is able to revert completely to sexually immaturity, colonial stage after reaching sexual maturity and is believed to be able to do so indefinitely, the jellyfish is biologically immortal. The transformation might be epigenetic under the condition of starvation, sudden temperature change, reduction in salinity or damage to the bell. Scientists have attempted to isolate the action and genetically engineer transgenic human cells to be infused into humans. (Dimberu, Peniel M. (2011-04-25). “Immortal Jellyfish Provides Clues for Regenerative Medicine”. Singularity Hub. Retrieved 26 October 2011). What is left to do is find the genetic structure of immortality in the jellyfish and copy over to transgenic mice and initiate the identical effect. The Hydra and the Salamander have amazing regeneration ability, cut off a limb and it grows back with no scar tissue. The naked mole rat does not age or gets sick with age. Lifespans: Arctica islandica and Ocean Quahog, shell fish both 500 years, Greenland shark 270 years, Bowhead Whales and Koi 200 years, Galapagos Giant Tortoise 150 years (all the above live in the ocean), Tuataras a reptile 150 years, Elephants 70 years and Humans. The shortest lived animals, Gastrotrichs a marine microorganism 3 days, Drone Ants 3 weeks, Houseflies 4 weeks, House mouse and Chameleon 1 year, Guinea pigs 4 years, Domestic rabbits 8-12 years. Animals have different lifespans suggesting hardwired lifespan. Scientists Find Mechanism That Extends Worm Lifespans by 500 Percent
Longest life span and possibly health span live around islands namely Sardinia, Okinawa (the United States of America has recently contaminated both these places with nuclear radiation from military training exercises). Water acts as a natural air and microbe purifier aiding in overall health, clean air, clean water, clean food resulting in health and life span. Wealthy people also live longer due to better conditions, in contrast people who face appalling conditions live about half as long. The West is hell-bent on trashing and destroying the planet, garbage, exhausts, chemicals, pollution of air, water and food is not fit for human consumption, it is advised to limit your intake of fish due to the increasing mercury levels caused by industrialization and many more practices that threaten all life on Earth. Health and life span has developed through evolution and evolution is used to explain why some activity might be healthy or unhealthy, e.g. pathologies of age are not eliminated by natural selection as offspring occur before onset of age related disease. Realistically no one can fix the body if it breaks so prevention is imperative, lead a healthy lifestyle. The best nutritional advice is not to eat at all instead fasting, the body works on air and water and very much less on food. Do cardio and weight training, secure good quality air, water, food and many other practices, walk barefoot on the sand, optimal sleeping practices and so on. If one cannot add days to life, then optimize lifestyle through the use of time and how you treat your own body. Some people limit their sleep to have more time, move relative to climate to gain more usable days and so on. Do not discount placebo effect as it is no small, insignificant statistical aberration, estimates of the placebo cure rate range from a low of 15 percent to a high of 72 percent. The longer the period of treatment and the larger the number of physician visits, the greater the placebo effect. Activate the placebo effect in your lifestyle. Great sex, great life. Think general health, the whole goal is staying pre-clinical out of hospitals and far from doctors for as long possible by healthy lifestyle. Look at the conditions of age and make your plan, you are looking for real ways to maintain muscle and tissue mass or strength especially the older you get, and avoid immune system function decline with age. The removal of blood clotting factors that rise with age and keeping your brain healthy and avoid diabetes.
Free radicals, oxidative stress is an older theory of ageing. A free radical is any atom or molecule that has a single unpaired electron in its outer shell causing chain reactions that damage surrounding cells. Over 90 diseases are attributed to oxidative stress. The assumption is electrons of atoms that form the human body can only be derived from food or pills, “anti-oxidants” but that is not the case. Food or pills are not the highest source of antioxidants and have become a way to market substances that have no real health benefit, a growing market of products are sold by the largest most trusted pharmaceutical companies under licence as “antioxidants” and “anti-inflammatory” fallaciously. However, electrons are in fact everywhere, the Earth contains electrons and the moment you touch earth you normalize the atoms in your body, if you need more electrons the Earth sends it up to you, if you have too many the Earth takes it back. Simply walk barefoot at the park, bathe in the ocean, but the most effective way of normalizing electrons is by electrically earthing the body overnight by sleeping grounded. As you sleep the causes of reactive species are remedied and you also supply mitochondria extra electrons for energy. While no products are necessary earthing pads are commonly used. It is about surface area, how much of your skin is touching earth. Grounding like gym exercise is session based, the benefits cover you for a period of time afterwards, every night . Z potential. The free radical theory of ageing has been replaced by damage theories of ageing, the sources of damage are radiation (AM/FM radio waves, television radio waves, satellite radio waves, Wifi, 3G-4G, cell phone tower radio waves, U.V rays note: we know sun damage is a cause of skin cancer, various other radiation and radioactive sources e.g. nuclear testing and nuclear reactor accidents, electro smog from electrical appliances, power lines expel electro-smog), chemicals, toxins, fumes and exhaust fumes in the air or in food and drink, ROS, stress, obesity and lack of exercise and natural processes that generate waste products during human cell process collected and flushed as urine. Damage vs. Repair. The body has repair mechanisms but there is no respite in an ever-increasing damaging environment. The amount of daily damage should not exceed the body's daily ability to repair. The majority of repair occurs during sleep. Therapies during sleep which totally eliminate sources of damage may prove as beneficial as exercise or fasting. Given, it is strange but a proposed therapy such as sleeping in a lead shielded or Faraday cage room or supply of atoms to the body such as electron and proton emitters is scientifically testable. Studies: Earthing Grounding Studies, Gut molecules implicated in early death from sleep deprivation
Rapamycin and Metformin, two touted drugs said to increase human lifespan. Metformin primary action is to inhibit mitochondrial complex 1 while Rapamycin pathway mTOR (mammalian target of rapamycin), mTor is further divided into mTor1 and mTor2 each group separate process. mTor is a growth regulator in relation to available nutrients, when mTor growth regulation is suppressed perhaps during puberty the organism grows to its maximum regardless of available nutrients where nutrients regulate the size of an organism. Metformin (a diabetes drug) is believed to mimic the benefits of exercise in a pill without any exercise, AMPK activation. People who have metabolic dysfunction gain from Metformin, while people who exercise or who already have optimal metabolic function not only achieve no gain from taking Metformin but it is counter-productive to them. Rapamycin (immune-suppressant drug) is believed to trigger autophagy something that occurs after fasting for 16 hours, autophagy improves cellular condition and the condition of every aspect of the cell is super important for health. Both these drugs have side effects with Rapamycin believed to be a weekly or twice a month drug with daily use being life-shortening and Metformin having no gain in healthy people or people without Type 2 diabetes. Sestrins (Sesns) are groups of proteins made when a person exercises, accumulate in the muscle and so the possibility of “eating” (big molecules not bioavailable) the proteins to mimic exercise. Stress-induced Sesn expression results in inhibition of the target of rapamycin complex 1 (TORC1). Can people with type 2 diabetes live longer than those without?, the study says No. Is Metformin Really an Anti-Aging Drug?, Gaf1 and ageing.
Sirtiuns are a class of proteins that possess either mono-ADP-ribosyltransferase, or deacylase activity, including deacetylase, desuccinylase, demalonylase, demyristoylase and depalmitoylase activity. Sirtuins regulate important biological pathways in bacteria, archaea and eukaryotes. The attempt to activate situins, promote biogenesis / homeostasis in mitochrondria, responsible for giving energy to cells. Sirtuin, Sirt 1,2,3,4,5,6,7 are a class of proteins responsible for metabolism, cell cycle, DNA repair and rRNA transcription. Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes such as DNA repair, genomic stability, and programmed cell death. STACs (small molecule sirtuin activators) are drugs for sirt activation, there are no STACs and no known pills that can trigger for example DNA repair. As of 2018, there was no clinical evidence that sirtuins affect human ageing. Emerging Anti-Ageing Strategies - Scientific Basis and Efficacy. It is believed that there are about 238 genes that can do healthy tasks like DNA repair. They have to fit it into a pill format for commercial purposes but 238 is way too much and breaks the pill format, forget 238 how about 6? Thanks for coming everyone, good night and drive safe. A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging A trick to activating "anti-aging" proteins in worms could exist in humans, too
Nicotinamide adenine dinucleotide, NAD+ a cofactor central to metabolism. With ageing, cell performance diminishes and production of proteins decrease while some increase. NAD+ is produced by the liver and said to decrease with age (almost every measure does with age). Low levels of NAD+ are said to decrease sirtiun or parp activity, acetylation and lifespan. People who supplement with NAD+ or a precursor generally feel no benefit, do not appear more youthful and have a placebo effect outlook. It is said that without NAD+ you would die, what does that even mean? Maybe similar to holding your breath too long or hiking in the desert without water. NMN is not bioavailable and Nicotinamide Riboside (NR) does not make it past the digestive system. Remember, Chromadex went live with NR before efficacy was proven, and they only done one small trial with conflict of interest to conclude their product was safe to eat. It is also a complex process, dumping substances into the bloodstream is too simplistic as there are domino effects, cascades, chain reactions. When people supplement the organ that normally produces that supplement loses its ability to do so, such as people who supplement with testosterone, their testicles shrink (hypogonadism) as it no longer produces the hormone, supplementing with NAD+ may cause the same situation, causing low NAD+ levels for more than a year or more after it is stopped secretly creating an addiction cycle, there are also methylation deficiency that arise from supplementation. It was also said that no matter how much dose was infused the body regulated the amount of NAD+ in the body disposing of excess. This leads to a greater question, why, does it decrease with age, is it another cell morphology causation? NAD+ fad supplementation is probably a scam. Pterostilbene sometimes sold as a substitute to Resveratrol which is destroyed by sulphuric acid of the stomach and not bio-available has even less evidence of efficacy. The advice is take Niacin, Vitamin B3 is a cheap yet equal substitute for expensive NR. I suspect that Vitamin B3 or NR is no more life extending or health promoting than any other vitamin. Clinical Trial of Nicotinamide Riboside Completed NAD+ Restoration Therapy - Risk-Benefit Analysis
Telomeres, there was that whole telomeres humdrum a while back. Telomeres are the strands at the end of DNA when they decrease in length ageing accelerates and when they get short the cell no longer divides. The body naturally produces telomerase to maintain telomeres and there are attempts to increase telomeres artificially using telomerase or gene therapy, both short and long telomere length cause disease processes with over lengthening causing cancer, Long telomeres and cancer risk: the price of cellular immortality. If a cell has DNA damage and short telomeres, extending the telomeres causing the cell to replicate multiplies the DNA damage although the body also has DNA repair mechanisms. Telomere shortening with cell division may then be a way to limit the cell proliferation relative to damage. Danazol may or may not be able to lengthen telomeres but has many side effects but generally not a cancer causing agent. Cycloastragenol is a molecule isolated from various species in the genus Astragalus that is purported to have telomerase activation activity. However, there are reports of liver cancer. Dyskeratosis congenita (DKC), also known as zinsser-engman-cole syndrome is characterized by short telomeres. Some manifestations resemble premature ageing (similar to progeria), it might be caused by a gene mutation inhibiting telomerase production. There is a maximum number of times cells can divide to form new cells, 40 to 60 times before they become senescent, called the Hayflick limit which sets the maximum potential human lifespan to 115 years. If telomeres length is able to be kept at the ideal length the potential for regeneration increases. Telomere length has been shown to positively correlate to life span, the other big one is stem cell progenitor cell depletion with age. Cells in the human body do not undergo mitosis at the same rate, some do not replicate at all and newly formed daughter cells are not formed with short telomeres, however aged cell morphology insights show short telomeres, decreased replication with age looks like dyskeratosis congenita and progeria. Can science design a therapy to maintain ideal telomere length in vivo. I doubt it. Study identifies potential drug treatments for telomere diseases Newly discovered interactions between proteins can reduce DNA damage and cancer development
Cdc42, bone marrow derived stem cells, haematopoietic stem cells and mesenchymal stem cells (multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts (bone cells), chondrocytes (cartilage cells), myocytes (muscle cells) and adipocytes (fat cells which give rise to marrow adipose tissue). As the body's stem cell generation factory ages it is said they come functional yet degraded from the beginning and in declining amounts. Cdc42 activity regulates haematopoietic stem cell ageing and rejuvenation. Department of Dermatology and Allergic Diseases, University of Ulm, 89091 Ulm, Germany 1,2. The decline in haematopoietic function seen during ageing involves a progressive reduction in the immune response and an increased incidence of myeloid malignancy, and has been linked to ageing of haematopoietic stem cells (HSCs). The molecular mechanisms underlying HSC aging remain unclear. In their paper they demonstrate that elevated activity of the small RhoGTPase Cdc42 in aged HSCs is causally linked to HSC ageing and correlates with a loss of polarity in aged HSCs. Pharmacological inhibition of Cdc42 activity functionally rejuvenates aged HSCs, increases the percentage of polarized cells in an aged HSC population, and restores the level and spatial distribution of histone H4 lysine 16 acetylation to a status similar to that seen in young HSCs. Their data suggests a mechanistic role for Cdc42 activity in HSC biology and epigenetic regulation, and identify Cdc42 activity as a pharmacological target for ameliorating stem cell ageing. (immuno-decline and pericyte activation). The prospect that HSCs and even MSCs could be kept very young invivo. This bone marrow stem cell production system is important in ageing relating to tissue degeneration and immune system decline as the two leading causes of death. Young Bone Marrow Rejuvenates Aging Mouse Brains, Study Finds
Senescent cells are damaged cells that are in cell cycle arrest, stopped from replicating but resident, accumulate with age and are thought to contribute to inflammation, tissue damage and age-related diseases. Senescent cells remove themselves or are removed by the immune system but with immune system decline senescent cells accumulate, immune system cell types are made in the body (bone marrow) and form part of blood composition. The innate process is called autophagy. Senescent cells secret senescent associated secretory phenotype (SASP), the increased expression and secretion of a suite of inflammatory cytokines, chemokines, growth factors, and proteases (Coppé et al., 2010a; van Deursen, 2014). Senescent cells are believed to suppress tumour but SASP may increase tumours. Senescent cells are believed to compound ageing in ageing bodies. There are drugs named senolytics that claim to clear senescent cells from the human body, the deleted senescent cells are replaced as part of the bodies natural process either when an adjacent cell divides or from bone marrow derived pericyte stem cell. These cells must be replaced with better cells and so an optimal cell replacement protocol is also required. Good housekeeping? The effectiveness of senolytic drugs in vivo is uncertain, perhaps removal of 50% of senescent cells with the actual amount varying widely by tissue and drug type - in some tissues, the effect is negligible for the drugs tried thus far. What is required is a highly effective senolytic in the 99% range, and also different types such as for cancer treatment and prevention, scar tissue removal, even pre-senolytic, anticipating cells that are showing first stages of damage, perhaps short telomeres senolytic. Their are also drugs called senomorphics that suppress SASP but do not kill the cell, we also know that senescent cells occur in the brain so suppression of SASP in the brain might prove important. Not one senoltyic is effective against every type of senescent cell in the human body, opting for the strategy of a combination or cocktail of senolytics. Once the sensescent cells are cleared their is no more reason to keep taking pills, it is said take high doses for up to a five days, once every year.
Using senolytics prior to stem cell infusion may or may not enhance the treatment The Clinical Potential of Senolytic Drugs Ageing, tumour necrosis factor-alpha (TNF-α) and atherosclerosis Senolytics and Senostatics: A Two-Pronged Approach to Target Cellular Senescence for Delaying Ageing and Age-Related Diseases Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases Scar-free healing: from embryonic mechanisms to adult therapeutic intervention Senescence can be BETter without the SASP? Suppression of the senescence-associated secretory phenotype (SASP) in human fibroblasts using small molecule inhibitors of p38 MAP kinase and MK2 Senolytic drugs: can this antibiotic treat symptoms of ageing?
Hypothalamus, reasoning to the hypothalamus is one organ having major importance to ageing while others have minor importance. What happens at the important organ goes systemic and the effect cascades, domino effects, chain reactions throughout the body, strategy is to identify and concentrate on the majors. The endocrine system with the hypothalamus being number one and the pituitary gland number two. The hypothalamus controls child growth phase, starts and ends puberty, initiates body changes for pregnancy and menopause and also knows how to keep time, the circadian rhythm or day/night cycle is in the hypothalamus. This small gland is in the most ancient part of the brain, the limbic system and is believed to keep time for an organism's lifespan. When the hypothalamus senses low oestrogen in the blood of a woman it sends a signal to the pituitary gland which in turn sends a signal to the ovaries to produce more oestrogen. Puberty occurs with clockwork regularity, the method and control of which is unknown, perhaps a neural clock perhaps accumulation of methylation acts as a clock, (telomeres can be interrupted as a type of cell division clock). That the circadian rhythm is in the hypothalamus makes the organ highly suspicious of being in part the timer for lifespan, such a master clock of the human body is called the (SCN) Suprachiasmatic nucleus consisting of 20,000 neurons, time keeping systems like these in the central nervous system may be dictating the lifespan of an organism. In this case averting death is similar to attempting to avoid puberty, regardless of what you do sooner of later it is going to happen. Centenarians, persons that live up to and past 100 years run in families and different animals have their specific lifespan both suggest genetic lifespan mechanism. Researchers at Albert Einstein College of Medicine conducted a study on mice. They discovered that as mice age, levels of molecules, specifically IKK-β and NF-kB, molecules that initiate inflammatory responses, increase in the brain, particularly in the hypothalamus. The concentration of the pro inflammatory cytokine tumour necrosis factor β also increases. The increases directly cause a decline in gonadotropin-releaseing hormone (GnRH). Mice that produced less IKK-β and NF-kB in the hypothalamus created more neurons and solved mazes more quickly, had greater muscle strength, and exhibited a 20% longer lifespan. The opposite effects were seen in mice that overproduced IKK-β and NF-kB. Zhang G et al. Hypothalamic programming of systemic ageing involving IKK-β, NF-kB and GnRH. Nature 2013 May 9; 497:211. Gabuzda D, Yankner BA. Physiology: Inflammation links ageing to the brain. Nature 2013 May 9; 497:197. Brain cells found to control ageing, Yalin Zhang, Min Soo Kim, Baosen Jia, Jingqi Yan, Juan Pablo Zuniga-Hertz, Cheng Han, Dongsheng Cai. Hypothalamic stem cells control ageing speed partly through exosomal miRNAs. Nature, 2017; DOI: 10.1038/nature23282, Has a small trial stumbled upon a way to reverse biological aging?
Trans-humanism, replacing body parts with “superior” mechanical prosthetics. Improving prosthetic technology has noble medical applications, the key is fusing bio with the mechanical permanently. Even a permanent IV-port useful for intravenous access appears highly undesirable. People want an arm, hand and fingers that are identical to their biological version in every way, from the effortless control of the limb to its dexterity and qualifying expectations, if it falls short then it fails completely. The major issue is that when a person loses an arm or a leg hospital duration is 6 months and rehabilitation takes years. The advantage is that metal lasts a very long time and is simpler than the body limb, living on Mars or on the Moon becomes applicable as no oxygen is required and the materials can handle the harsh environments. In the process, eventually only the brain will remain and so on. I doubt this will ever be. Biomedical engineering are machines that do some function of the human body such as a lung machine or tools for medical work such as blood purifying, processing machine, these machines are nowhere near organ replacement solutions. The group that says humans download their brain to a mainframe, they will exist virtually until a clone is made and the technology exists to download the virtual self back into the clone. Those that are attempting to grow new organs using stem cells will eventually create a brainless clone (doubt it will ever happen). The head transplant experiment a while back should never to be tried again, plagued with far too many issues, has to fade into history and that chapter closed. Cryogenics is freezing oneself and then unfreezing oneself after a time, the guy offered the service without a way to unfreeze them, which is completely bizarre. If they could unfreeze them before offering the service that would be better probably not using ice, a person dissatisfied with the modern age would say, put me under and wake me in a hundred years and in a hundred years, wake them up, spend a year looking around and say nope, put me under for another one hundred years. I think this could be the wildest service out there, but the technology of cryogenic has not moved at all. How to make Voltron? Call four sexy friends “Form Voltron, activate interlock, Go Voltron Force” I prefer Mighty Morphin' Power Rangers. Oh, continue reading then…
Hormone therapy, ageing people should probably be on a personalized hormone therapy or doing exercises to promote hormone production. Hormones are the first way to make a person feel as though they are not ageing even if not reverse ageing. Hormones will affect strength and energy levels, libido and mood. The problem with hormone therapy is there is no easy way to add hormones, the dystrophy to the endocrine system such as the testicles and that can lead to over a year of no production of hormones after the treatment is stopped, understanding safe levels, the health effect of a hormone and if a hormone does what we believe it does. Hormones release a person from a catch 22, less exercise due to reduced hormone levels leading to frailty, instead more and harder exercise decreasing frailty. An older person cannot physically achieve cardio. Does the key to anti-ageing lie in our bones?
What diseases resemble ageing? Progeria, Cutis Laxa…
Progeria (one of several progeroid syndromes) is an extremely rare autosomal dominant genetic disorder in which symptoms resembling aspects of ageing are manifested at a very early age. Those born with progeria typically live to their mid-teens to early twenties. Progeria is caused by gene mutations that weaken the structure of the cell nucleus, making normal cell division difficult. The histone mark H4K20me3 is involved in Hutchinson-Gilford Progeria syndrome caused by de novo mutations that occurs in a gene that encodes lamin A. Lamin A is made but is not processed properly. This poor processing creates an abnormal nuclear morphology and disorganized heterochromatin. We just assume that ageing is progeria and as people age they are experiencing a form of progeria, while not Lamin A identical instead conceptually identical. A myriad of cell biology pathology like misfolded proteins and like progeria a normal human ageing cell also distorts, the rate of cell division also decreases and senescence increases and along with many other known cell biology problems. As organs age for example the pituitary gland begin to lag in performance, becomes deformed, lumpy and shrunken with age and like nuclear deformation in progeria the cell deformation in ageing causes similar problems. See how visually the shape of nucleus tells of a problem, with age the cell also starts to have these kinds of defects. When doctors speaks of fatty acid build up, leaky blood brain barrier, hearing, sight or some other situation what they are really saying is your cells have genetic mutations or epigenetic markers showing up as cell morphology pathologies. The cell's dysfunction is a much larger problem that continues unaddressed, their medications do not address this understanding and when critical, death will result. Inbreeding also expresses defects in the genome that present as pathology, the likelihood of health issues and early death is increased. If they cannot cure progeria, they will not be able to cure ageing, if they can not turn on and turn off puberty at the genetic level, they will not be able to cure ageing, if they cannot regenerate tooth in old age, then they will not be able to cure ageing. Such is the reality check. Progeria is the key insight. Removing Wrinkles Inside Our Cells Might Reverse Aging
Cutis laxa is a disease that makes people appear far older than they are. Biopsies have shown reduction and degeneration of dermal elastic fibres in the affected areas of skin. Cutis laxa is associated with deficient or absent elastin fibers in the extracellular matrix. This can be related to decreased elastin synthesis or structural defects in the extracellular matrix. It can be inherited or acquired, known as acquired cutis laxa, some people have symptoms but do not have the associated genetic changes.
The ways that proteins generally fail are…
It is believed that the cause differs but all result in sub-optimal elastin fibers. Is the protein perfect on exiting the cell or is it damaged enroute? A recent study suggests the presence of monoclonal gammopathy is strongly associated with several dermatological entities such as acquired cutis laxa 1. Cutis laxa has recently been found in patients with abnormal glycosylation. The majority of inborn errors presenting with cutis laxa are related to abnormal Golgi function and frequently related to transport defects and abnormal protein glycosylation. Contrary to patients with Golgi system-related cutis laxa forms, those with PYCR1 and MAP kinase pathway defects show no glycosylation abnormalities. In some of these children mild mitochondrial dysfunction has been observed, but usually they do not manifest metabolic markers of mitochondrial disease 1. It has also been considered that mutations in elastin (ELN) and fibulin-5 (FBLN5) genes can increase susceptibility of elastic fibres to inflammatory degradation in acquired cutis laxa. Idiopathic inflammation and allergic (or other) reactions to medicines such as penicillin, isoniazide and D-penicillamine. Further, preceding factors are hematologic abnormalities like plasma cell dyscrasias and congenital hemolytic anemia, which causes localized acral cutis laxa, as well as infections, especially Borrelia burgdorferi. Other inciting inflammatory disorders like urticaria, angioedema, rheumatoid arthritis, systemic lupus eythematosus, erythema multiforme, nephrotic syndorme, celiac disease and dermatitis herpetiformis have been reported. Finally, it has been associated with paraneoplasia. Type II (Marshall syndrome) occurs in infants and toddlers and develops in response to acute inflammatory skin lesions. Rare associations with alpha 1 antitrypsin deficiency, arthropod bites and Sweet's syndrome have been described. Degradation of elastic fibres through proteolyitc processes is believed to play a role in acquired cutis laxa. This concept is supported by the presence of tissue elastases released after activation of polymorphonuclear leukocytes and monocyte-macrophages in an inflammatory event. IgG and IgA deposits in lesional skin and paraproteinemia have also been reported and raise the possibility of an immunopathogenetically mediated process. Autosomal Dominant Cutis Laxa (ADCL) is caused by mutations in the Elastin (ELN) gene. MACS syndrome is caused by mutations in the RIN2 gene. Gerodermia Osteodysplasticum (GO) is caused by mutations in the GORAB (SCYL1BP1) gene. Occipital Horn Syndrome is caused by mutations in the ATP7A gene. Changes/mutations in the following genes cause each of the subtypes of Autosomal Recessive Cutis Laxa (ARCL): ARCL1A: Caused by a mutation in the FBLN5 gene, ARCL1B: Caused by a mutation in the FBLN4 (EFEMP2) gene, ARCL1C: Caused by a mutation in the LTBP4 gene, ARCL2A: Caused by a mutation in the ATP6V0A2 gene, ARCL2B: Caused by a mutation in the PYCR1 gene, ARCL3: Caused by a mutation in the ALDH18A1 gene. People with these subtypes are also found to have mutations in the PYCR1 and ATP6V0A2 genes. Cutis laxa may be caused by mutations in the genes: ELN, ATP6V0A2, ATP7A, FBLN4, FBLN5, and PYCR1. A related neurocutaneous syndrome may be caused by mutations in the gene ALDH18A1 (P5CS). Cutis laxa may also be seen in association with inherited connective tissue disorders such as Ehlers–Danlos syndromes. Another syndrome associated with cutis laxa is Lenz-Majewski syndrome which is due to a mutation in the phosphatidylserine synthase 1 (PTDSS1) gene. Most of these genes are involved in the formation and function of elastic fibres, which are slender bundles of proteins that provide strength and flexibility to connective tissue throughout the body. Elastic fibres allow the skin to stretch, the lungs to expand and contract, and arteries to handle blood flowing through them at high pressure. The major component of elastic fibres, a protein called elastin, is produced from the ELN gene. Other proteins that appear to have critical roles in the assembly of elastic fibres are produced from the EFEMP2, FBLN5, and ATP6V0A2 genes. Mutations in any of these genes disrupt the formation, assembly, or function of elastic fibres. A shortage of these fibres weakens connective tissue in the skin, arteries, lungs, and other organs. These defects in connective tissue underlie the major features of cutis laxa. 28 year-old woman who looks 80 with “ageing” disorder undergoes Plastic Surgery Mitochondria in skin health, aging, and disease Generalized Acquired Cutis Laxa Associated with Monoclonal Gammopathy of Dermatological Significance The extraordinary 'Benjamin Button' children with wrinkly skin condition which makes them look years older
Gene therapy, it is believed that ageing and death is genetic and gene therapy is the way to immortality. In a study, monozygotic twins are formed when one zygote, one egg and one sperm, splits into two and have similar lengths of life when compared to dizygotic twins, two ovums, two sperms1, inclining that identical genetics equals identical lifespan. The difference with each child of the same parents is the chromosomes are shuffled leading to wider range of differences, do dizygotic twins relative to parents born of the same parents but not twins? All children born from the same parents are believed to have the same mitochondria, does the monozygotic twins study disprove the mitochondria theory? Centenarians, persons that live more than 100 years run in families we would assert is genetic. Genetic mutations cause many diseases and increase with age. The body has a genetic repair system, and gene therapy to treat. For our purposes we require error checking; check for error condition, if found then repair, otherwise do nothing. Their are several methods of interest, Crispr Cas 9 in an engineered exosome, their is a Crispr version that checks for a condition to code some RNA and Crispr is also used for Epigenome editing. The latest news is that Crispr Cas 9 has been improved 96 fold against off site editing. Gene therapy is essential for ageing treatment. New CRISPR enzyme mutation proves almost 100 times more precise An engineered exosome for delivering sgRNA:Cas9 ribonucleoprotein complex and genome editing in recipient cells Articles: Neuroscientists discover anti-aging molecule that repairs age-related DNA damage Synchronized age-related gene expression changes across multiple tissues in human and the link to complex diseases Single-gene treatment cures mice of Parkinson's within three months Distal lung epithelial progenitor cell function declines with age Studies find CRISPR gene-editing of human embryos give rise to unwanted results.
Jumping Genes, known as transposable elements or transposons — Transposons are self-replicating sequences of DNA that copy and paste themselves throughout the genome (some kinds can also cut and paste themselves). In a way, transposons are viruses that do not like to travel outside the confines of a cell. They do very much the same thing as viral sequences, i.e. make copies of themselves and infect genomes. Some retroviral sequences in the human genome (very old viruses that infected our ancestors and still exist in our DNA) are themselves transposons. Because these transposable elements are mobile they have a disturbing capacity to disrupt important genes by inserting themselves into the DNA sequences and transposons seem to preferentially insert themselves into important and functional genes. Furthermore, because transposons can rapidly alter the DNA sequences in your genome they are thought to play a major role in the processes of evolution and speciation (how one species evolves into a new one). Jumping genes good or bad? Studies show they play a good role while others say bad role. Inhibition of 'jumping genes' promotes healthy ageing, 'Jumping genes' drive many cancers. To jump, transposons express RNA which is translated into proteins called transposases. Transposases allow the transposon to move from place to place in the genome. This scrambled DNA expresses scrambled RNA that can be recognized by the cell as “foreign.” This RNA is chopped up into small fragments, which can be used to identify, target and degrade RNA from normal copies of the transposon. This prevents those transposons from making protein, and thus prevents them from jumping. Purdue scientists identify genetic ‘immune system’ for junk DNA
Horvath age estimation algorithm (2013), found 353 epigenetic bio markers of human ageing, according to which the chronological age of a person can be determined to an accuracy of 1.5 years, your death date can be predicted to an accuracy of 1.5 years. These epigenetic bio marker measurements are not fixed and can change depending on lifestyle, like fasting or exercising so a practice can be investigated to be beneficial or not by its effect on the Horvath age estimation algorithm. The Horvath age estimation algorithm predicts DNAm age based on the methylation levels of 353 CpGs. DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts to repress gene transcription. In mammals, DNA methylation is essential for normal development and is associated with a number of key processes including genomic imprinting, X-chromosome inactivation, repression of transposable elements, ageing, and carcinogenesis. Correlation or causation? It is leaning towards causation. There are other biomarker systems to test efficacy of proposed experimental treatments or therapies, any advice currently based on peer reviewed studies also is at the mercy of biological clocks such as the Horvath age estimation algorithm. A person can be tested prior to a therapy and then tested again after to determine value of a proposed therapy. Biomarker signatures of aging
Epigenome editing, the blueprint to build a human is DNA, genes, genetics, genome. Genes within the XX chromosome builds a girl and XY chromosome builds a boy (sperms make both and adds one during conception). The ovum is a cell and divides to form the human complete, so the human body completely consists of cells and every cell in the human body contains a full copy of the DNA or genome. Not all cells are the same, there are eye, skin, bone, muscle cells and more. So how can they be different? The epigenome is a system that can turn parts of the genome off or on, this is called gene expression, some genes are expressed while others are not without changing the underlying genome. Certain reptiles have an environmental determinate, e.g. hot outside, a male versus cold outside, a female because the temperature communicates with the epigenetic system to express relative to temperature. You can regrow your teeth in old age, it is still in the DNA but the epigenome is keeping that ability locked away, so the ability to communicate with the epigenome is the ongoing challenge. Just like the reptiles, our lifestyle also communicates with the epigenome and using the Horvath age estimation algorithm, we can try some alteration to lifestyle, chemical, restriction… and see if it effects the epigenetic bio markers determine if the behaviour is “healthy” or not. The epigenome is seen as the holy grail, if the epigenome was reset to that of a young person, a person would never age or die. We await the landmark paper, controlled modulation of the epigenome and its effect on ageing. Crispr is used for epigenome manipulation. Epigenome editing, Genetic brain disorder fixed in mice using precision epigenome editing, A new epigenetic editing tool is developed to activate silenced genes, but information on how to localize the treatment or histones. Precision epigenome editing can repair genetic syndrome of intellectual disability TET Enzymes The ageing epigenome and its rejuvenation
Cancer, many advanced regenerative therapies potentially cause cancer such as pluripotent stem cells or telomere lengthening. These are candidates to make such therapies safe. A lab will have tested a candidate and paired it to a therapy and if teratoma occurs, an injection will successfully remove those cells completely. No problem. There is also some interest in pre-emptive cancer prevention injection, perhaps 1 injection every 10 years. Here is an untested list of candidates for labs to investigate further. Sodium dichloroacetate (DCA) might act against cancer cells by depolarizing abnormal mitochondria found in glioblastoma cancer cells – allowing the mitochondria to induce apoptosis (cell death) of the malignant cells. In vitro work with DCA on neuroblastomas (which have fewer recognized mitochondrial abnormalities) showed activity against malignant, undifferentiated cells. Metabolic Modulation of Glioblastoma with Dichloroacetate Metabolic Modulation of Glioblastoma With Dichloroacetate. Some cancer cells share traits with healthy cells, which keeps the immune system from detecting them as problems. Researchers changed the genes in his T cells – white blood cells that survey the body for infections and other invaders to recognize and attack his leukaemia. After researchers remade Wright's cells in the lab, he got them back through an IV. Then everyone waited for him to get a fever, a sign the T cells are working. Immune system ate the caner.1. Some vaccines can help prevent — or even treat — certain types of cancer. For example, the human papilloma virus (HPV) vaccine protects against many types of HPV that can cause cervical cancer. Vaccine Sipuleucel-T used to treat advanced prostate cancer that hasn’t responded to other treatments. T-cell therapy, CAR T-cell therapy, Monoclonal antibodies. 1, MR1 Therapy1 Why Do Elephants Rarely Get Cancer?. Theoretically DNA repair is possible, gene mutation is repirable systemically if the agent is ignored if it does not find its target and no off base alterations, as a known aging related mutation gene therapy platform and support for DNA repair.
Young blood or parabiosis, although when we discuss ageing, we are only really referring to one experiment, parabiosis. By surgically connecting a young mouse to an old mouse so that they share a common blood stream, it is said the blood supply of the young mouse causes the old mouse to get younger. In the mid-1800s, parabiotic experiments were pioneered by Paul Bert. He postulated that surgically connected animals could share a circulatory system.
The old mouse gets younger but the young mouse gets older. Is it the young blood or the young organs? A television show that evoked interest named Silicon Valley episode The Blood Boy depicts human to human parabiosis as a practice of the eccentric wealthy. Next, a company called Ambrosia by Jesse Karmazin went live with blood transfusions using young blood, some laughed, some cheered, some scorned, but they were attacked by the US government and forced to shut down, (should have operated out of Central America like the growing list of US medicals in exile). At the same time the well established colleges were working to understand the results of parabiosis for the prospect of a cash cow pill. The concept is the gold standard is the blood of a young athletic person. Wait, what? Umbilical cord blood, Wharton's jelly. OK, here goes. Bone marrow, adipose, embryonic, placenta, fetal, induced pluripotent (ipsc), amniotic tissue, Wharton's jelly cord tissue are a source of stem cells while umbilical cord blood, amniotic fluid and blood composition relative to age are a source of blood factors. Not strictly, there might be cells in fluids and factors in tissue but the study differs. Factors are molecular chemical structures while more complex cells are the building blocks of the body. This section strictly relates to blood composition differences with age or blood factors, while not eliminating any valid factors, the reference, blueprint or comparison is the biological difference between the blood of a young athlete and every one else and can be measured.
So it was a simple matter of blood transfusion with young blood? According to Tony Wyss-Coray, young people have levels of blood factors (components in blood) that are rejuvenating and old people have levels of blood factors that promote ageing, age promoting secretions increase and age demoting secretions decrease. This made the proposed therapy more technical, suggesting that blood transfusion is incorrect by cause some blood factors need to be added while other blood factors require removal or just synchronize the blood composition to that of a young person. The theoretical therapy would be an exchange transfusion which means total replacement of blood, 5 litres of blood out and 5 litres of blood in, which is the most complex form of blood transfusion although performed around the world routinely, successfully. There are protocols to follow for professional transfusion practice and you should be well-trained in the protocols before attempting blood exchange. Blood transfusions from strangers are not rejected, like transplanted organs. As the source of blood is a young person, there are technical and supply issues as this therapy is not a serious medical use of blood, those interested in blood composition experimentation require a safe, cosmetic protocol, one that does not require “blood from children”, a procedure would be only take the ageing factors out and only add rejuvenating factors using synthetic factors. See apheresis.
A recent study, Reversing age: dual species measurement of epigenetic age with a single clock, the results are significant enough to prompt further interest.
College labs in their search for a cash cow pill prompted them to dissect blood, but they were soon disappointed as the complexity of the human body cannot be treated in a pill. Interested parties put resources into isolating a single protein but that possibility is long gone and much of the interest with it. While, one protein cannot make it rain perhaps one protein might still be useful for some pathology. Reluctantly, we are led into the labyrinth of factors. What are the factors? What is the formula? And will the results be any better than parabiosis? In a recent paper by Irina & Michael Conboy known as “the Conboys”. Diluted blood plasma found to reverse ageing in mice suggest by replacing the plasma of mice with a “neutral” mixture they achieved the same or better tissue rejuvenating results as parabiosis. They did not add young blood factors, instead they removed some blood and injected saline/albumin neutral replacement to achieve the same results. Mystery deepens, some say albumin is not a neutral substitute. According to the Conboys, 1. the increase in ageing factors are due to the deficient performance of organs in an ageing person, in a young person the organs maintain the proteome, answer to the parabiosis question of organs vs. blood. 2. Ageing factors have a dominant effect when compared to youthful factors to such a degree that extracting ageing factors is enough to slow ageing even without adding youthful factors. Dilution of ageing factors meaning there are less ageing factors total in blood. They report that injecting young blood into an old mouse is not beneficial, but injecting old blood into a young mouse is devastating to the young mouse. It has also been stated previously that heating the blood cancelled its rejuvenating factors, discrepancy? We know that heat destroys both cells and proteins. I do not think the body is producing extra bits in blood for no reason, factors is still in the mentality, however they make the point that effective serum in vitro might be the ideal media in vivo and exceeding performance of insitu plasma is possible and the therapy a simple dilution.
The last implications the Conboys put forward is speculative, that maybe there are no factors at all and that the benefits come from an interruption in intercellular communication, perhaps if the cell is not reacting to a condition then it better uses time to do some housekeeping or its homeostasis is subjective to signals from the external environment rather than its actual state.
Whole blood, plasma only or major factors, what will deliver the best results? What about going synthetic? What about a computer composition machine where tens of thousands of proteins can be auto analysed and auto normalized?
There are those who do not believe in the whole blood thing, but they ought to ask themselves; How are cells grown and maintained in a petri dish? It is blood that provides the nutrients along side the cells so that they can live. It is called fetal bovine serum, blood from a cow foetus sustains cells in a petri dish. In vitro as the serum degrades starvation leads to reduced cell survival, increased apoptosis and wide-ranging effects on cell health, quality and rates of expansion, media needs to be replaced every 24 hours for cells to keep on living. In vivo the media is blood, the analogue is identical. The composition of media in vivo degrades with age and cascades “ageing” until the body breaks. As blood deviates with ageing in quality, levels, ratio and composition, cells alter their homeostatis and eventually die. The media provides two effects, one is nutrients for the cell material structure and other is epigenetic communication. Egypt is a gift of the Nile, all that the body manufactures is probably found in the bloodstream with 20,000 to over 100,000 proteins, enzymes, signal molecules, secretome and many types of cells analysing each one is a monumental feat let alone synthesizing. As well as providing nutrients for cells, it is believed components in blood communicate with the epigenome to regulate cellular condition. There are 2 to 3 thousand G protein-coupled receptors (GPCR's constitute a large protein family of receptors that detect molecules outside the cell and activate internal signal transduction pathways and, ultimately, cellular responses, see ligands & receptors) in each cell accessing, switching genes constantly, what we send into the blood also speaks to the genetics. A function of homeostasis. If the cell detects bad media it will re-configure itself.
What is believed to be causing ageing? Ageing can be thought of as being in the progeria family of disease, in progeria a DNA mutation causes nuclear morphology dysfunction inhibiting cell division leading to an ageing like appearance, with dyskeratosis congenita (DKC) a genetic mutation in telomerase results in short telomeres, cell division also inhibited. With age cells exhibit a range of morphology disorders which is visually apparent and apparent under microscope. It is not all DNA errors, the body intentionally down regulates, such as the amount of stem cells at birth compared to age which limits regeneration ability. Cell morphology disorders mean the cell cannot perform mitosis, the result is cells do not get replaced, senescent cells increase and their ability to function degrades until something critical breaks and then, Goodnight Irene. The treatment is supplementation, provide the cells with high quality nutrients that can constitute their material structure, provide high quality proteome to override the degraded proteome, e.g. iron accumulation in the brain is said to be caused by misfolded proteins, blood normalization does not rectify the folding of the proteins within the cell but instead supplies correctly folded proteins directly, overriding, so that iron can again be metabolized. Increase the capacity of the stem cell regenerative system to counter regenerative system decline, gene therapy to correct genetic mutations and correcting epigenetic configuration. Each of the three sections in the picture represent an ability to represent the ideal state which is a young person or a baby or a centenarian to reference against. Its divides health by blood composition, organ/cell condition and genetic/epigenetic configuration. The news is we can already implement an optimal blood composition but the cell condition and epigenetic configuration are incomplete technologies.
We need to continue to research the reasons and causes of why cells appear less like a young person and more like an old person and propose therapy. We are not using any pharmaceutical drugs or side effects, these are what the human body works with on its own. Instead, rectifying the alteration in composition that appears with age. If we can enrich the blood, we believe that overall health would improve. Comparing old and young blood composition and synchronizing is not cell biology, it does not answer all questions and it does not suppose to, but instead if delivered intelligently keep a person pre-clinical for longer.
More studies: Undulating Changes in Human Plasma Proteome Profiles Across the Lifespan Blood serum study reveals networks of proteins that impact aging Plasma Proteomic Signature of Age in Healthy Humans Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice Role of circulating factors in cardiac aging Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment Scientists Find Surprising Age-Related Protein Waves In Blood AMBAR, an Encouraging Alzheimer's Trial That Raises Questions Scaling the Alzheimer’s Cure Ability to eliminate spent proteins influences brain aging and individual life span Protein Folding: The Good, the Bad, and the Ugly
We want to upgrade the apheresis machine to do full blood composition auto analysis and auto normalization using both apheresis and pheresis and using a synthetic haemo product. This we believe will have a positive organ/cellular, epigenetic and in turn haemographical improvement slowing ageing and related pathologies. We know what the optimal blood composition should be, the blood composition of many athletes and centenarians in their prime is the blueprint, and we can safely implement that blueprint in another person ongoing. Most other forms of regenerative medicine are injections or drip infusions, blood normalization is more complex and requires some components of blood removed while other components added and other measurements such as viscosity and condition of the cellular portions of blood. The Conboy paper says at the very least all we need to do is remove senescent ageing factors, no additives, no foreign blood required but haematology has extensive off the shelf knowledge to offer that we should incorporate to better achieve by measure blood synchronization of blood composition with young blood and even include exotic factors like TIMP2 but strictly no drugs or side effects. Using a custom apheresis machine made especially for the role, here is an example of what a machine could be like. The machine in the video takes a specified component out of blood and then returns the same blood, our machine needs to analyse and take components out of blood while also add specified factors. Rather than sample, filter, centrifuge, normalize each protein individually or 20,000-100,000 proteins, the complexity of the machine could be minimized by removing dominant ageing factors in an effort to cause a beneficial cascade on the rest of the proteome automatically such as chaperones and proteasomes (see protein misfolding). We envision a monthly commercial cosmetic treatment. No packages, everyone gets the complete makeover with the aim of taking the system from state to another state with diminishing treatment required with each session because of improvement.
The industry has to decide if it prefers plasma exchange or re-conditioning existing blood/plasma. In plasma exchange when bag of plasma is replaced, a bag of plasma remains surplus which can go back to the blood bank. This commercial cosmetic practice can pay donors potentially increasing whole blood/plasma supply for medical use vs. apheresis that requires either little to no hetero blood instead the existing blood is conditioned and additives sourced by synthetic equivalents, just like testosterone is synthesized. The synthetic route eliminates transfusion reactions as it uses no donor blood.
Fetal Bovine Serum, all cell culture therapies rely upon fetal bovine serum. FBS is not a fully defined medium because defining the medium takes too much work but the industry must find animal free FBS alternatives. Fully Define and Synthesize Fetal Bovine Serum For Industrialization of Lab Meat FCS-free Database A change in (cell) culture: exploring alternatives to fetal calf serum
The leading causes of death of people over 65 suggest factors for….
Vitamins, Minerals, Amino acids, quantity and condition of cells, see Blood Composition
Here is a small list of major identified factors,
Demethylation Targets, these are not proteins, these are gene expression targets for epigenetic editing e.g. Crispr/Antisense demethylation targets.
Complete haemo normalization is possible today.
Hemorheological Changes During Human Aging Hemodynamic changes during aging associated with cerebral blood flow and impaired cognitive function Red blood cell deformability during storage: towards functional proteomics and metabolomics in the Blood Bank Immune cell transplant reverses effects of aging in mice
Mesenchymal Stem Cells and Exosomes, we have heard of the immune system but the human body also has its own regenerative system, the human body has a complex system that performs self-healing, simply if we cut ourselves the body heals. It's all about taking these healing and repair systems to their ultimate level.
Mesenchymal stem cells do repair work, and they hone in using inflammation, without secretion of inflammatory factors they do not know where to go. You cannot eat turmeric or grape juice to ameliorate inflammation. Inflammation is the initial response to tissue damage or cell damage, when a person cuts themselves or bumps their head the area becomes inflamed or swells. After that the human body activates its regenerative system to begin the repair process. Inflammation increases with ageing and this may be due to the difference in cell morphology relative to a young person and the body views an aged cell as damaged and thus the inflammatory response, the remedy is then the innate regenerative response, which is severely limited with age so a foreign source of the components of the regenerative system is infused. There are various places that stem cells can be harvested, bone marrow or fat tissue but the stem cells there are at the same age as the patient, the richest source of these regenerative factors is in umbilical cord, Wharton's jelly, amniotic tissue, placenta. The stem cells in focus are mesenchymal stem cells and exosomes. They take these cells, expand them in culture and infuse or inject them into an older person, where they hone in on inflammation and conduct systemic repair work (apoptosis, cleaning, signal adjacent cells into mitosis and more). Non bone marrow or fat tissue cells do not have matching DNA with the recipient, but they are said to have immunomodulation abilities for a period, they communicate with the immune system to get a pass for a time but eventually the immune system eats them. There is still no way to have young stem cells become part of the foreign body due to immune system rejection which could be an unrealized potential as stem cell depletion is a major indicator of ageing. These sources of stem cells are ethical if they are expanded using non-animal serums otherwise they use foetal bovine serum which is unethical and the field has a very evil temptation of using aborted babies as a source of ideal stem cells, in some places abortion laws have been quietly altered to facilitate the harvesting of aborted babies. Foetal stem cells are the remains of aborted babies and there are some ugly people that want to absorb them. Which should I have, exosomes or mesenchymal stem cells or both? Exosomes are extracted from mesenchymal stem cells, as it is believed that exosomes from healthy cells carry much of the regenerative proteins of mesenchymal stem cells and also exosomes fit the definition of nan particles. Nano particles are very small and can penetrate the blood brain barrier in hopes it regenerates the brain. It is believed that much or all of the positive outcomes believed to have been attributed to mesenchymal stem cells for the treatment of neurodegenerative disorders are due to the exosomes derived from mesenchymal stem cells. Many scientists now believe that you are skipping right to the regeneration process by using exosomes as opposed to mesenchymal stem cells. MSC fan boys say, you need the full signalling capacity of which only the MSCs can provide and not just the exosome. Exosomes have messenger RNA, micro RNA and proteins and are made by cells and transfer these contents to other cells. Cells produce exosomes, so there might be a way to make a transgenic cow that produces human exosomes in the milk, already shown to be possible using mice Do the microRNAs we eat affect gene expression?, as they are nan particles they are bio-available and the milk orally consumed. Not all exosomes are identical, the constituting RNA and proteins are information and can communicate differently so the age of the cell is important here, as young exosomes are communicating different information than old exosomes, so exosomes produced by a theoretical transgenic cow would have to code for the right types or mix of one or more optimal exosomes. There are several places where you can receive an injection of mesenchymal stem cells or exosomes, some claim great success others not. I do not believe that bone marrow or adipose stem cells are effective in comparison to umbilical cord derived stem cells. The therapy is required either every year or every three years and constitutes one IV session lasting one hour, with beneficial effects progressing over several months. Some say they have had better results with senolytic treatment prior and some say slim down and get fit before getting them. Expertise is crucial, the most established practitioners are possibly the Riordan clinic in Panama (MSCs), and PRmedica exosome clinic in Mexico. A session might cost $10,000 (USD), unless they have opted for non-animal serum stem cell therapies rely on foetal serum to grow stem cells. Extracellular Vesicles, Ageing, and Therapeutic Interventions, Stem Cell-Derived Exosomes Prevent Aging-Induced Cardiac Dysfunction through a Novel Exosome/lncRNA MALAT1/NF-κB/TNF-α Signaling Pathway, Biotech companies leading the way with exosome human clinical trials, Mesenchymal Stem Cells for Regenerative Medicine Therapeutic repair for spinal cord injury: combinatory approaches to address a multifaceted problem
Yamanaka Factors by Shinya Yamanaka, transcription factors are proteins that bind to DNA-regulatory sequences (enhancers and silencers), to modulate the rate of gene transcription. This may result in increased or decreased gene transcription, protein synthesis, and subsequent altered cellular function. Yamanaka factors are a group of transcription factors, 4 proteins injected into the cell or bathed in medium that can turn a differentiated cell back into an embryonic stage cell just like Turritopsis dohrnii, the immortal jerry fish and also re-differentiate cells from for example a skin cell back to embryo and then into a liver cell if given the right chemical signals. These are adult stem cells called IPSC (induced pluripotent stem cells). In 2006 Dr. Shinya Yamanaka, a stem-cell researcher at Kyoto University, amazed biologists by showing that a cell's fate could be reversed with a set of four transcription factors — agents that activate genes — that he had identified. A cell dosed with the Yamanaka factors erases the marks on the epigenome, so the cell loses its identity and reverts to the embryonic state. Erroneous marks gathered during aging are also lost in the process, restoring the cell to its state of youth. Dr. Yamanaka shared the 2012 Nobel Prize in medicine for the work. In age reversal we do not want to turn the cells back into embryonic stage. Before this everyone thought the cells cycle was fixed in one direction only. Yamanaka factors are (Oct3/4, Sox2, Klf4, c-Myc) are highly expressed in embryonic stem (ES) cells, and their over-expression can induce pluripotency in both mouse and human somatic cells, indicating that these factors regulate the developmental signalling network necessary for embryonic stem cell pluripotency. In 2016, Juan Carlos Izpisua Belmonte, of the Salk Institute for Biological Studies in San Diego, found that the two effects of the Yamanaka factors — erasing cell identity and reversing ageing — could be separated, with a lower dose securing just age reversal. He achieved this by genetically engineering mice, but if a mouse gets too much the cell becomes an embryo and starts dividing leading to cancers, tumours. Izpisúa Belmonte believed there might be a way to give mice a less lethal dose of reprogramming. He was inspired by salamanders, which can regrow an arm or tail. Researchers have yet to determine exactly how amphibians do this, but one theory is that it happens through a process of epigenetic resetting similar to what the Yamanaka factors achieve, though more limited in scope. With salamanders, their cells “just go back a little bit” in time, Izpisúa Belmonte says. In 2016, Belmonte's team devised a way to partially rewind the cells in mice with progeria. They genetically modified the mice to produce the Yamanaka factors in their bodies with condition the mice would produce those factors only when given an antibiotic, doxycycline. Some mice were allowed to drink water containing doxycycline continuously while others got it just for two days out of every seven. “When you give them … doxycycline, expression of the genes starts,” explains Reddy. “The moment you remove it, the expression of the genes stops. You can easily turn it on or off.” The mice that drank the most quickly died. But the mice that drank a limited dose did not develop tumours. Instead, they became more physically robust, their kidneys and spleens worked better, and their hearts pumped harder. In all, the treated mice lived 30% longer than their littermates. A Stanford team confirmed Salk Institute, extracted aged cartilage cells from patients with osteoarthritis and found that after a low dosage of Yamanaka factors the cells no longer secreted the inflammatory factors that provoke the disease and also found that human muscle stem cells, which are impaired in a muscle-wasting disease, could be restored to youth. Members of the Stanford team have formed a company, Turn Biotechnologies, to develop therapies for osteoarthritis and other diseases. Another company is AgeX and GenuCure developing various treatments, heart tissues, osteoarthritis, aging-related muscle loss, rejuvenating cartilage. 1 Other scientists are experimenting with the factors, by leaving some out or another derivative cell quality improves and cancer is less probable while others are including more factors than the four, OSKM. The major problem is separating ageing from ipsc, they are struggling to get significant age reversal before going too far, high dose and reverting the cell to ipsc. They are using RNA's which degrade quickly, have no permanent effect and have the possibility to be systemic perhaps in a vesicle. It matters less as to effectiveness at this stage rather, any proposed therapy even modest be safe. The situation might require a reprogramming blocker, after an RNA partially reprograms, another RNA makes the cell immune to further re-programming allowing systemic uniform partial reprogramming. The RNA will eventually dissolve and the cell becomes partially reprogrammable again. Yamanaki prolonged life mice by 50
We have not been able to take advantage of new stem cells, embryonic stem cells or IPSCs replacing aged tissue cells as a regenertive treatment, so here is a theoretical therapy.
The body is 100% made of cells, cell morphology including genetics, epigenetics are the source and cause of many pathologies, cell quality is important. Cells degrade and get damaged and most are replaced, with age even replacement cells come defective from the beginning. Human beings have an estimated 30 to 40 trillion cells in total, no one knows for sure in the human body. Cells are highly complex and need to function correctly and optimally all the time for a person to be “healthy”. It is estimated that each day 50 to 70 billion cells die (signalled to self-destruct, apoptoses) and are replaced as part of body's natural process. Cell replication is called mitosis, some cells can divide (skin cells) and use a neighbouring skin cell to replace a cell, other cells partially lose their ability to replicate (liver cells) and require the body's regenerative system, mesenchymal stem cells to activate non dividing cells into mitosis, while other cells lose their ability to repair such as brain neurons and are never replaced. Various people argue for saving the cell as if the exact same cells exist in the body for ones entire life, in fact the body replaces cells ongoing to maintain optimal body. Do liver stem cells come from bone marrow One-time treatment generates new neurons, eliminates Parkinson's disease in mice.
Some organs are highly regenerative while some not, it is often stated that on average, cells in a human body are replaced every 7 to 10 years. Red blood cells 4 months, white blood cells over 1 year. Skin cells: 2 or 3 weeks. Colon cells: ~4 days. Brain cells typically last an entire lifetime (neurons in the cerebral cortex, for example, are not replaced when they die). Neutrophil cells (a type of white blood cell) might only last 2 days, while the cells in the middle of your eye lenses will last your entire life. Brain cells: 200+ years? Eye lens cells: Lifetime, Heart muscle cells: 40 years, Intestinal cells (excluding lining): 15.9 years, Skeletal muscle cells: 15.1 years, Fat cells: 8 years, Haematopoietic stem cells: 5 years, liver cells: 10-16 months, Pancreas cells: 1 year and so on.
When 50 to 70 billion cells die each day and are replaced, how do we get better cells to take their place? Not only the 50 to 70 billion cells each day but also as a regeneration and maintenance of organs in situ therapy. Unless we can upgrade the condition of these replacement cells, ageing will occur.
Grading cells to see if they are functioning completely correctly at an optimal level does not happen, is not a therapy. The pharmaceutical cell removal agents called synolytics are also of questionable effectiveness. The immune system plays the major role of daily disposal of damaged cells, there is autophagy after fasting, but we do not manually verify, detect and remedy damaged cells. Can we say cell number 1 trillion does not have the stop sequence or potassium delivery in cell number 2 trillion is sub-optimal? There seems to be nucleus deformation on cell 1 billion? Sub-optimal ATP production in mitochondria cell number 7 trillion and so on. Tag those and remove, that would be the right procedure to perform. There is no M.R.I like machine that can perform this task on a cell by cell basis.
The obvious therapy might be to manufacture the higher quality cells outside the body and then introduce them into the body (ex in vitro) along with the various additional proteins the body dispatches when there is a wound. These cells are younger than existing cells in the body and with a sophisticated treatment the body is kept from ageing by providing young cells, practically biologically new cells that the body cannot achieve on its own.
The reason we have not seen large scale stem cell treatments is immune system rejection, just like in organ transplants. The field is called “stem cell immunobiology”. They have been saying for over 10 years that stem cells have the potential to create organs without immune rejection. That is not the case.
Groups seek to produce off the shelf stem cell product that is not rejected by the immune system. To quote Dr. Sonja Schrepfer “Our team used CRISPR to create the first pluripotent stem cells that are functionally 'invisible' to the immune system, a feat of biological engineering that prevents rejection of stem cell transplants and brings the promise of regenerative medicine a step closer to becoming reality” and “In our paper, we describe how, by altering the activity of just three genes in pluripotent stem cells, these triple-engineered stem cells are able to avoid rejection after being transplanted into histocompatibility-mismatched recipients with fully functional immune systems.” Hypo immunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients. The first time I heard of this was by Claudia Mitchell, Ph.D., CEO Seattle, WA of Universal Cells in 2017. AgeX Therapeutics and Sernova to Collaborate to Engineer Universal Locally Immune Protected Cell Therapies for Type I Diabetes and Hemophilia A, its trial use in humans dated June 2020.
Mesenchymal stems are able to go to the destination of inflammation and differentiate in tissue cells without teratoma formation. Why can't stem cells do the same?
If what she states is correct, it will be possible to have modest cell replacement therapies. These cells offer regenerative medicine and it is all that we want. But… in my opinion, the immune system cloak of knocking the three genes come with potential problems. The function of these three genes is so the immune system can detect and destroy the cell because it is malfunctioning and without this monitoring of the cell, when these universal cells become dysfunctional the immune system is blind to their state. If a virus gets into one of these cells it will replicate indefinitely and the immune system will be blind to where it is coming from and the person will die. These problems need to be remedied otherwise the cells will not be fit for use. Its solution might be in finding biomarkers of cell dysfunction and attaching those markers to apoptoses using genetic engineering, or there might be other ways for universal stem cells to pass the immune system check without gene editing and that would be a better case. What if the cells are generated in the body, does the familiar environment provide some critical identification factor making them pass the immune system? Due to these unknowns the universal stem cell is sub-standard to a healthy human, but a step up for a sick person.
It has the potential to make humans partially transgenic. One of these cells take up residence in the human body, that body is regarded as transgenic. Transgenic means Genetic Engineering Or Genetic Therapy. These cells can be genetically engineered to do any actions as much as intelligence can instil in a cell. The stem cell is a programming platform, hopefully an open source platform. Once that cell is expanded the genetic program is in every cell. This may begin with a modest 0.001% transgenic human and increase with popularity of the therapy with an eventual maximum possible transgenic percentage. A transgenic embryo to reference is a 100% transgenic person, because the genetically engineered first cell is replicated to every cell afterwards.
Such a therapy for universal stem cells, each month a person would come in and be infused with a bag of universal stem cells, as the body is replacing cells all the time the infused cells are incorporated. These stem cells are younger than the body's cells and also have special abilities that have been genetically coded into them. If a person has an issue with an organ that requires organ transplant, intentional wounds are made to the organ in order to remove as many diseased cells in a session, this can be done using a sonic scalpel called histotripsy can destroy a certain amount of for example liver cells in the patient (who has the liver problem). This is will cause the body to attempt to repair the wound, at the same time inject the patient with universal stem cells (along with the identical mixture the such MSC's) and hope the body utilizes the lab grown cells instead of the body's cells for the repair. Repeat the procedure until the liver is replaced. Scar free healing is a field of regenerative medicine.
Scar tissue treatments, cirrhosis, scarring (fibrosis), there are no systemic pharmaceutical agents for scar tissue removal. Envisage an injection that targets the fibrosis cell and apoptoses. This is a field called scar free healing, Scar-free healing: from embryonic mechanisms to adult therapeutic intervention. Scar free healing is used in conjuction with scar tissue pharmaceutical agents.
It is a simple idea, the ongoing continual renewal of cells from young universal stem cells has the potential to have a major effect on ageing. No person is able to get younger cells replacing their current cells, due to the immune system so it is uncertain what effect it would have. If the crucial to ageing organs and cells were biologically new and kept biologically new in an ageing body, perhaps it will lead to the discovery of organs relating to longer lifespan.
Improving the safety of human pluripotent stem cell therapies using genome-edited orthogonal safeguards
Advances in production of retinal cells for treating blindness
Direct in vivo application of induced pluripotent stem cells is feasible and can be safe
Why Does Your Body Reject Your Own Stem Cells?
Transplants without Immunosuppressant Drugs UCSFs Transplant and Stem Cell Immunobiology Lab Finding Genius Podcast with Dr. Schrepfer and Dr. Deuse.
This procedure utilizes the Yamanaka factors as a theoretical therapy. Firstly, in normal humans and secondly in transgenic humans. The major problem here as with genetic vectors is how do get systemic, 1 cell, 1 dose. Systemic means each cell in the body gets the same dose. With transgenic the alteration is specified in the ovum and replicated throughout the organism, allowing for uniform activation later on. As genetic engineers do not have such a level of control without going transgenic, such reveals that effective Yamanaka factors treatment have not been used in humans, possibly other than some haphazard lysate or a vector for self experimentation.
Old people should be able to regenerate new teeth when they fall out just as young people do. Gene expression control theoretically would allow for the activation of tooth regeneration in an old person, where is it? The code to do this still exists for a persons entire life but is locked from expression. How to turn it back on? What is important is that Yamanaka factors are also still in the human genome. If we can regenerate teeth we could also partially activate Yamanaka factors. Currently, no means to control genetics easily. Partial reprogramming in vivo is not outrageous, there are some real potential medical applications discussed openly.
A list of papers…
In vivo amelioration of age-associated hallmarks by partial reprogramming
In vivo transient and partial cell reprogramming to pluripotency as a therapeutic tool for neurodegenerative diseases
Partial reprogramming in vivo enhances wound repair in mice
Regeneration through reprogramming adult cell identity in vivo
Aging, cell and tissue repair, renewal and regeneration, inflammation and the sasp
In vivo reprogramming for brain and spinal cord repair
In vivo reprogramming of adult somatic cells to pluripotency by overexpression of Yamanaka factors
In vivo cellular reprogramming: The next generation
AAV vector-mediated in vivo reprogramming into pluripotency
De novo mutations in mitochondrial DNA of IPSCs produce immunogenic neoepitopes in mice and humans
Partial cellular reprogramming reverse aging
Immersed In A Pool Of Water
Fully body immersion in a pool of water, a lysate with Yamanka factors possibly as naked RNA. The time spent in immersion relative to dose can be generally controlled, while not an internal therapy, instead a skin therapy, external therapy. Simple, safe, easy. These kinds of small controllable therapies allow for safe study on humans.
Traditional Gene Therapy In Humans
A safe protocol for Yamanaka factor therapy in humans.
The major issue is if the dose is too much, the cell becomes an induced pluripotent stem cell, leading to cancer or death. It has been established that the right dose reverses ageing markers in a linear curve that ends at age 0. How do you deliver the correct dosage into the body, some cells will overdose while others will not receive any. If you infuse, it will concentrate around the liver or kidney with overdose effects. You need to control where it goes and the more control you have over cell dosage the better the treatment.
The only therapy that I heard about is, custom RNA using an exosome. The exosome is produced ex in vitro and then infused, it travels until it enters a cell where it releases RNA and the cell produces the Yamanaka factors. Both the RNA and exosome will eventually dissolve and a repeat infusion at some time interval.
Say for example you got a cow producing your custom exosomes with factors in milk and you harvest them or whatever. The ideal case in infusion is every cell gets 1 dose with 1 infusion. The closest to that goal is the ideal practice but how do you guarantee appropriate dose?
Yamanaka Factor Therapy has been tried in transgenic mice without effect of overdose but how systemic was the activation?
Bring the body to uniform systemic partial preprogramming with safety, Theoretical procedure is, exosomes are injected into the body. These exosomes have custom RNA that code for Yamanaka factors. These will enter cells randomly, the problem is many exosomes entering the same cell means over production of OKSM and full reprogramming. To remedy this, we also encode the RNA to produce an OSKM neutralizing molecule. After a certain number of factors are produced, extra molecules are also produced, having affinity for Oct8 and binding to Oct8 thus neutralizing Yamanaka factors rendering the further cell reprogramming immune. The extra production of the neutralizing molecule means any new exosome making their way into the same cell will be disabled (ideally from making factors) not from making factors, instead neutralized from effecting the cell further. This all done in sync will allow for one treatment to be fairly uniform, systemic and safe against full reprogramming. It is assumed that adding a molecule to Oct4 will disable Yamanaka factors. Eventually the cell will be cleaned out and immunity cleared away and subsequent treatment can occur again. Exosomes are made by cells for intercellular communication containing RNA and proteins. Agonist or Antagonist.
Secondly, looking at the matter as probabilities and ascertaining the best protocol based on probabilities. Dosage, injection area and dispersion area. Many small doses rather than one big dose and so on. Some cell will never receive a dose, while some will receive every dose. Targeting areas or organs by place of injection.
Thirdly, there are some cells that concentrate relative to cell signalling system, such as certain stem cells that concentrate around inflammation. These behaviours might localize the effect and aid in probability, because once the inflammation is dissolved the gene therapy will not go there twice. Inflammation might be a positive tag for the treatment.
Fourthly, liquid engineering, a dispersion lysate. A lysate added to the infusion to aid in a more ideal dispersion and against multiple infection of the same cell.
Fifthly, there are approximately three thousand GPCRs receptors on each cell, cell receptors for example produce vitamin D in response to light. Is there one that allows for favourable manipulation to control a vector, for the purpose of single dose to a single cell and binding for the duration of the treatment. Control the vector by magnetism. Beta blockers. Systemic AAV Vectors for Widespread and Targeted Gene Delivery in Rodents
There are possibly several more methods raising the bar to an acceptable level, at the very least probably experiment with a skin cream to test the saturation and dispersion. The challenge is one of expertise, optimization, ironing out the quirks. This therapy is not extreme or invasive but requires expertise. The path is mice, dogs, test and experiment on human skin, organs, and finally full body infusion.
Transgenic Human Experiment
Once a human being has reached maturity it has trillions of cells, with respect to gene therapy we have lost the ability to communicate with each individual cell, we just do not have that kind of technology. Instead, if we designed the genetic program, we could tell an ovum and when the body is made from that ovum our program will be replicated in every cell after that, meaning we can then communicate with every cell in that human body. This is called “transgenic human”.
The germ line edited ovum will grow into a human being and our gene therapy will be systemic, such a person able to have extra abilities, with one ability at the highest, “safe Yamanaka factor expression in a transgenic human experiment”.
This experiment will answer many questions and put many theories to rest.
Such a person would momentarily turn on safe Yamanaka factor expression with stimuli under clinical observation. Such a person would maintain an ideal physical age in every appearance and measure, even if the person were to be of age 70, they would always look and feel like a 21-year-old.
This will obviously need to be a secret experiment, to answer as many science questions as possible. Mainly, if the transgenic human never ages, why does the transgenic human still die?
The experiment is currently possible to do, but may take ample time to perfect the genetic program for safety and success. If we can get it right we would have our ethics backwards, the transgenic human will live a normal life but never age, instead stop ageing at their ideal age. An ability we would all like to have. If the person wanted to age normally they would opt not to express the factors and age normally with no further involvement.
If the experiment was done well, parents would opt for this procedure for their unborn children and humans would be replaced, so we must never tell of the existence of such people. The program would include….
The largest other reason people want to do this is to make super intelligent humans. The Chinese government is working on this but it is more like eugenics, genetics crossed with selective breeding.
That is a wrap, we are out. I hope you have enjoyed the article. There are several companies with deep pockets working on the field, we may not know what they know. There are many people who die every day and there are many people in a terminal state some conscious some not. Being sure to exclude psychopathic, moronic, sadistic, insane, dangerous, invasive and painful procedures, they really have none to lose.