From the Salk Institute in La Jolla, CA came an announcement last week that the four factors previously identified to turn ordinary cells into stem cells (in cell cultures) was successfully used as a rejuvenation procedure in live mice. \u00a0The results provide important new evidence for the hypothesis that aging is under epigenetic control, and a proof of principle that we might slow aging by modifying the chromosome markers and attachments that determine gene expression. \u00a0But the way in which this was done involved genetic engineering before birth, and there is no obvious way to translate the results quickly into an anti-aging teatment for living humans.<\/i><\/p>\n
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Ten years ago, Shinya Yamanaka\u2019s Kyoto University laboratory announced<\/a> that just four proteins could turn an ordinary, differentiated cell back into the stem cell from whence it came. \u00a0The four were transcription factors, high level switches that turn whole systems of genes on and off with one signal, and the \u201cYamanaka factors\u201d became known by their initials, OSKM.<\/p>\n Last week, Izpisua Delmonte\u2019s laboratory at the Salk Institute announced<\/a> a success in rejuvenating whole animals, live mice, using the same OSKM.<\/p>\n Whether this is the germ of a potent new rejuvenation treatment remains to be seen; but the immediate message is a dramatic affirmation of the new paradigm in anti-aging medicine: aging can be reversed by signaling, without artificially-engineered repair of damage. \u00a0A bold form of this paradigm is the epigenetic hypothesis<\/a>\u2014now just 4 years old<\/a>\u2014which says that aging is controlled by gene expression. \u00a0It is the set of genes that are turned on and off, and the genes\u2019 levels of expression that determine the state of the body\u2019s age. \u00a0(This idea does not deny that tissues and biomolecules suffer damage with age; but the hypothesis says that the body knew how to repair this damage at one time, and is capable of repairing the damage again, when the signal molecules engage repair mechanisms appropriately for a young individual.)<\/p>\n Gene expression \u00a0is controlled, in turn, by markers on the chromosome and on the histone spool around which the DNA is wrapped like thread on a spool. \u00a0These markers are known to change with age<\/a> in a characteristic pattern. \u00a0Shifting epigenetic markers program all the stages of development, and (according to the hypothesis), the program continues, and causes the body to pass through the stages of aging.<\/p>\n But in nature this clock never goes backward. \u00a0The epigenetic clock is reset to zero as the genome is wiped clean and reprogrammed. \u00a0This happens twice: once in the creation of germ cells, the sperm and egg; and a second time after sperm and egg join to make a zygote. \u00a0(This is a simplification; some traits are epigenetically inherited, implying that some genome markers are retained and pass across generations.)<\/p>\n If we buy the epigenetic hypothesis, then the holy grail of anti-aging medicine would be to reset all the epigenetic markers, say from age 60 to age 20, but not all the way back to zero. \u00a0This must be \u201cpossible\u201d in some sense of the word; but if it depends on us to read (for example) the methylation of a 20-year-old\u2019s chromosomes and write the results onto the chromosomes of a 60-year-old, in every cell of the body, without otherwise disrupting the living organism, then the task is daunting. \u00a0And methylation is just one of about 100 known epigenetic modifications of the chromatin.<\/p>\n Nature knows how to reset the epigenetic clock all the way to age 0, but there is no precedent for a partial reset. <\/i><\/b>\u00a0All tissue differentiation is lost, and the growth rate is pedal-to-the-metal high. \u00a0It should be no surprise that previous attempts to rejuvenate the living mouse by resetting the clock with OSKM have led to cancer disasters [ref<\/a>, ref<\/a>]. \u00a0In this new report, the Salk researchers used short, intermittent exposure to OSKM to \u201cpartially reset\u201d the epigenome. \u00a0If this really works, and if the epigenetic hypothesis continues to pan out, then this is indeed a week to celebrate.<\/p>\n <\/p>\n The experiment<\/b><\/p>\n The procedure was first tested in human cell cultures, demonstrating \u201cpartial de-differentiation\u201d, where functional cells were rejuvenated without returning them completely to stem cell status. \u00a0This was an important proof of concept. \u00a0The authors cite previous experiments<\/a> suggesting that OSKM re-setting is a multi-step process, so it is possible in principle to halt the process after partial re-programming, and hope for a somewhat younger state.<\/p>\n Next, the procedure was tested on mice with genetically short life spans, living an average of \u00a0just 18 weeks. \u00a0Mice with the OSKM treatment lived 24 weeks. \u00a0Impressively, the treatment was tuned so that it did not increase cancer rates. \u00a0The particular life-shortening gene was defective LMNA (Lamin A<\/a>). \u00a0Lamin A is important for structure and function in the cell nucleus (details hazy), and there is no way to distinguish from this experiment whether the OSKM treatment merely counteracts the deficiency of Lamin A or whether it slows aging generally. Finally, the procedure was tested in normal, aged mice. \u00a0They showed signs of improved healing, nerve regrowth, and mitochondrial chemistry typical of younger mice. \u00a0But the mice were sacrificed to determine these things, so there was no demonstration of increased lifespan for genetically normal mice. \u00a0Sometimes \u201cpublish or perish\u201d pressure leads researchers to kill the goose that lays the golden egg\u2026<\/p>\n But the big asterisk on this new result\u00a0is that the delivery system was through a gene added to the mice at the egg stage. \u00a0It is easy to modify genes at the egg stage, when there is just one cell, and then the modification is copied in every cell of the adult;\u00a0but to do gene therapy for\u00a0adult humans is still at an early experimental stage. \u00a0Every cell in their bodies had an extra copy of each of the 4 genes for the OSKM factors, and these genes were so configured that they could be turned on and off with a drug (doxycycline). \u00a0Administration of the drug was arranged to be just right to reprogram the cells, but not all the way. \u00a0Optimum was found to be a low dose, just two days a week.<\/p>\n <\/p>\n Theoretical hedging <\/b><\/p>\n Bench scientists have learned to adopt the epigenetic hypothesis in practice, but some are still bound to the obsolete theoretical ideas, inherited from sclerotic thinking about \u201cselfish genes<\/a>\u201d. \u00a0Belmonte was quoted<\/a> as saying the epigenome becomes \u201cdamaged\u201d late in life \u201cAt the end of life there are many marks and it is difficult for the cell to read them.\u201d<\/p>\n But studies of aging epigenomics show that in addition to random changes in the epigenetic state, there are definite, programmed changes\u2014enough to make an accurate epigenetic clock\u2014and that some of these changes turn down cell repair functions and turn up inflammation. \u00a0Aging involves a loss of order (\u201cdamage\u201d), but it also entails a set of programmed changes. \u00a0It is the latter that we may hope to address through a streamlined, signaling approach to anti-aging medicine, and, if we are lucky, the body may take up the ball from here and undo part or all of the damage.<\/p>\n <\/p>\n The bottom line<\/b><\/p>\n This is an important new confirmation of the epigenetic hypothesis. \u00a0Previous confirmations were<\/p>\n This new experiment shows that epigenetic changes can extend lifespan. \u00a0But the experiment offers no clear extrapolation to life extension for humans. \u00a0The treatment depends on four large molecules that need to be delivered to every cell nucleus in the body. \u00a0These molecules cannot be taken orally because they will not survive digestion, and even intravenous delivery will not get the molecules to cell nuclei where they are needed.<\/p>\n In cell cultures with the OSKM factors applied externally, stem cell yields are still just a few percent, even after ten years of experience.<\/p>\n The Salk researchers got around this by inserting the OSKM genes into the cell, but for already-living humans this is not a possibility. \u00a0The best we know how to do is to modify some<\/i><\/b> of the body\u2019s cells with gene therapy; CRISPR in living humans<\/a> is itself a new technique in its experimental phase.<\/p>\n So for the foreseeable future, I see a two-pronged approach to cell-level rejuvenation. \u00a0One is to remove senescent cells (senolytics<\/a>); and the other is stem cell removal, rejuvenation, multiplication in vitro<\/i>, and return to the body. \u00a0OSKM may be useful in this second step, rejuvenation of stem cells in vivo<\/i>.<\/p>\n","protected":false},"excerpt":{"rendered":"\n