{"id":599,"date":"2017-08-07T22:38:56","date_gmt":"2017-08-07T22:38:56","guid":{"rendered":"http:\/\/joshmitteldorf.peachpuff-wolverine-566518.hostingersite.com\/?p=599"},"modified":"2023-12-11T19:50:43","modified_gmt":"2023-12-11T19:50:43","slug":"building-the-case-that-aging-is-controlled-from-the-brain","status":"publish","type":"post","link":"https:\/\/scienceblog.com\/joshmitteldorf\/2017\/08\/07\/building-the-case-that-aging-is-controlled-from-the-brain\/","title":{"rendered":"Building the Case that Aging is Controlled from the Brain"},"content":{"rendered":"<p><i><span style=\"font-weight: 400\">Last week, a <\/span><\/i><a href=\"https:\/\/www.nature.com\/nature\/journal\/v548\/n7665\/pdf\/nature23282.pdf\"><i><span style=\"font-weight: 400\">new study<\/span><\/i><\/a><i><span style=\"font-weight: 400\"> came out fingering the hypothalamus as locus of a clock that modulates aging. \u00a0This encourages those of us who entertain the most optimistic scenarios for anti-aging medicine. \u00a0Could it be that altering the biochemistry of one tiny control center might effect global rejuvenation? \u00a0<\/span><\/i><\/p>\n<p><span style=\"font-weight: 400\">First some background\u2026.<\/span><\/p>\n<p>I have staked my career on the interpretation that aging unfolds under the body\u2019s full control. \u00a0Even those aspects of aging that look like random damage are actually damage that is permitted to accumulate as the body pulls back its defense mechanisms late in life and dials up some biochemical processes that look an awful lot like deliberate self-destruction<\/p>\n<p><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/25341512\">I believe<\/a> that aging is governed by an internal biological clock, or several semi-independent and redundant clocks. \u00a0There are<\/p>\n<ul>\n<li>A telomere clock, counting cell divisions on a flexible schedule, eventually producing <a href=\"https:\/\/scienceblog.com\/joshmitteldorf\/2015\/03\/13\/kill-senescent-cells-before-they-kill-you\/\">cells with short-telomeres<\/a> that poison us.<\/li>\n<li>The <a href=\"https:\/\/scienceblog.com\/joshmitteldorf\/2014\/11\/24\/three-technologies-to-watch\/\">thymus<\/a>, crucial training ground for our white blood cells, shrinks through a lifetime.<\/li>\n<li>An <a href=\"https:\/\/scienceblog.com\/joshmitteldorf\/2016\/12\/31\/epigenetics-and-the-direction-of-anti-aging-science\/\">epigenetic clock<\/a> alters gene expression over time in directions that give rise to self-destruction.<\/li>\n<li>A neuroendocrine clock in the <a href=\"https:\/\/scienceblog.com\/joshmitteldorf\/2015\/06\/12\/is-there-an-aging-clock-in-the-hypothalamus\/\">hypothalamus<\/a><\/li>\n<li>Perhaps other clocks, yet to be identified.<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-large aligncenter\" src=\"http:\/\/brainmadesimple.com\/uploads\/7\/8\/8\/5\/7885523\/_1397040.jpg\" width=\"332\" height=\"240\" \/><\/p>\n<p><span style=\"font-weight: 400\">A dream is to be able to reset the hands of the clock. \u00a0If we\u2019re lucky, then changing the state of some metabolic subsystem will not just temper the rate at which we age, but actually restore the body to a younger state. \u00a0Most of the research in anti-aging medicine is still devoted to ways to engineer fixes for damage the body has allowed to accumulate; but I belong to a wild-eyed contingent that thinks the body can do its own fixing if we understand the signaling language well enough to speak the word \u201cyouth\u201d in the body\u2019s native biochemical tongue.<\/span><\/p>\n<p><span style=\"font-weight: 400\">Some of these clocks are more accessible and easier to manipulate than others. \u00a0The epigenetic clock is most daunting, because it presents the spectre of a global network of signal molecules circulating in the blood, transcription factors that mutually support one another in a state of slowly-shifting homeostasis. \u00a0This system could be so complex that it might take decades to understand, and then hundreds of different signal molecules in the blood would need to be re-balanced in order to recreate homeostasis in a younger condition. \u00a0(For several years, the <a href=\"https:\/\/www.fightaging.org\/archives\/2017\/02\/an-interview-with-irina-and-michael-conboy-on-blood-factors-in-aging\/\">Mike and Irina Conboy<\/a>\u00a0have been looking for a small subset of molecules that might control the rest, but in a private conversation they recently told me they are less optimistic that a small number of factors controls all the rest.)<\/span><\/p>\n<p><span style=\"font-weight: 400\">At the other end of the spectrum, the hypothalamic clock presents the most optimistic scenario. \u00a0It is tightly localized in a tiny region of the brain, and might be relatively easy to manipulate, with consequences that rejuvenate the entire body. \u00a0The hypothalamic clock hypothesis is an attractive target for research because, if correct, it will offer direct and straightforward control over the body\u2019s metabolic age.<\/span><\/p>\n<p><span style=\"font-weight: 400\">That aging unfolds according to an internal clock remains a controversial claim, but what everyone agrees is that the body has some way to know how old it is. \u00a0There has to be a clock for development that determines when growth surges and stops, when sex hormones turn on and, if it\u2019s not too great a stretch, when fertility ends and menopause unfolds.<\/span><\/p>\n<p><span style=\"font-weight: 400\">The clock that governs growth and development has yet to be elucidated\u2014a major metabolic mystery by my lights. \u00a0The clock that we know about and (sort of) understand is the circadian day-night clock that governs sleep and waking, giving us energy at some times of the day but not others.<\/span><\/p>\n<p><span style=\"font-weight: 400\">Is the life history clock linked to the circadian clock? \u00a0Maybe the body just counts days to tell how old it is? \u00a0This possibility was eliminated, at least for flies, using experiments with cycles of light and dark that were consistently longer or shorter than 24 hours. \u00a0Flies living with fast day-night cycles (less than 24 hours) lived shorter, as predicted; but flies living with long day-night cycles failed to have longer lifetimes, \u00a0In fact, deviation from 24 hours in either direction shorten the fly\u2019s lifespan [<\/span><a href=\"http:\/\/www.tandfonline.com\/doi\/abs\/10.1080\/07420520500179423\"><span style=\"font-weight: 400\">2005<\/span><\/a><span style=\"font-weight: 400\">]. \u00a0<\/span><\/p>\n<p><span style=\"font-weight: 400\">But this study suggests the short-term clock and the long-term clock may be linked in a way that is less straightforward. \u00a0Melatonin may be another reason to expect a connection. \u00a0Melatonin is the body\u2019s cue for sleep, and <\/span><a href=\"http:\/\/www.sciencedirect.com\/science\/article\/pii\/S0005272806000673\"><span style=\"font-weight: 400\">Russian studies<\/span><\/a><span style=\"font-weight: 400\"> have documented a role for melatonin in aging. \u00a0A third motivation comes from the fact that aging disrupts sleep cycles, and (in a downward spiral) disrupted sleep cycles are also a <\/span><a href=\"https:\/\/scienceblog.com\/joshmitteldorf\/2014\/09\/08\/sleep-and-longevity\/\"><span style=\"font-weight: 400\">risk factor for mortality<\/span><\/a><span style=\"font-weight: 400\"> and diseases of old age.<\/span><\/p>\n<p><span style=\"font-weight: 400\">Cells seem to have their own, built-in daily rhythms. \u00a0I want to say \u201ctranscriptional rhythms\u201d, adding the idea that gene transcription is the locus of control; however, red blood cells are the counterexample\u2014they exhibit daily cycles, even though they have no DNA to transcribe [<\/span><a href=\"https:\/\/www.nature.com\/nature\/journal\/v469\/n7331\/abs\/nature09702.html\"><span style=\"font-weight: 400\">2011<\/span><\/a><span style=\"font-weight: 400\">]. \u00a0Individual cycles are designed to be 24 hours, but they would soon drift out of phase with day and night if they weren\u2019t centrally coordinated. \u00a0The reference clock that keeps the others in line is in the SCN, the <\/span><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/18032104\"><span style=\"font-weight: 400\">suprachiasmatic nucleus<\/span><\/a><span style=\"font-weight: 400\">, a handful of nerve cells in a neuroendocrine part of the brain called the hypothalamus.<\/span><\/p>\n<p><span style=\"font-weight: 400\">Think of a million pendulums that are all tuned to swing with a period of 24 hours. \u00a0All that it takes is a tiny nudge to all these pendulums each day to keep them in phase with one another, so they are all swinging together. \u00a0The SCN provides this nudge in a smart way, based on information from the eyes (light and dark) and endocrine signals that indicate activity and sleep. \u00a0The SCN is upstream of the pineal gland, and supplies the signal that tells the pineal gland when it\u2019s time to make melatonin. \u00a0The natural resonances of individual cells become entrained in a body-wide response. <\/span><\/p>\n<p>&nbsp;<\/p>\n<p><b>What does all this have to do with aging?<\/b><\/p>\n<p>Experiments in the 1980s and 90s showed that the SCN is related to annual cycles, but the relationship seems to be not as strong or as simple or as direct. \u00a0For example, squirrels in which the SCN was removed had no daily sleep-wake cycles at all, but their annual cycles of fertility and oscillations of weight were affected inconsistently, more in some animals than others. \u00a0Transplanting a SCN from young hamsters into old hamsters cut their mortality rate by more than half, and extended their life expectancies by 4 months [<a href=\"http:\/\/journals.sagepub.com\/doi\/abs\/10.1177\/074873098129000255\">1998<\/a>].<\/p>\n<p>I have written in this column [<a href=\"https:\/\/scienceblog.com\/joshmitteldorf\/2015\/06\/12\/is-there-an-aging-clock-in-the-hypothalamus\/\">one<\/a>, <a href=\"https:\/\/scienceblog.com\/joshmitteldorf\/2016\/01\/29\/is-aging-controlled-from-the-brain-npy-and-alk5\/\">two<\/a>] about research from the laboratory of <a href=\"http:\/\/neuroendocrinologyandaging-cnc.weebly.com\/\">Claudia Cavadas<\/a> (U of Coimbra, near Lisbon) indicating that inflammation and inflammatory cytokines in the hypothalamus are at the headwaters of a cascade of signals that lead to whole-body aging. \u00a0They have emphasized the role of TGF\u00df binding to ALK5 and of the neurotransmitter NPY. \u00a0We usually think of inflammation as a source of damage throughout the body, but in the hypothalamus, inflammation seems to have a role that is more insidious than this, with full-body repercussions. \u00a0Blocking inflammation in the hypothalamus is a promising anti-aging strategy.<\/p>\n<p><b>New Paper on micro RNAs from the Hypothalamus<\/b><\/p>\n<p>Along with Cavadas, <a href=\"http:\/\/www.einstein.yu.edu\/faculty\/11603\/dongsheng-cai\/\">Dongshen Cai<\/a> (Einstein College of Medicine) has been a leader in exploring neuroendocrine control of aging that originates in the hypothalamus. \u00a0Several years ago, Cai\u2019s group <a href=\"https:\/\/www.nature.com\/nature\/journal\/v497\/n7448\/full\/nature12143.html\">demonstrated<\/a> that aging could be slowed in mice by inhibiting the inflammatory cytokine NF-kB and the related cytokine IKK-\u00df just in one tiny area of the brain, the hypothalamus. \u00a0\u201cIn conclusion, the hypothalamus has a programmatic role in ageing development via immune\u2013neuroendocrine integration\u2026\u201d \u00a0They summarized findings from their own lab, suggesting that metabolic syndrome, glucose intolerance, weight gain and hypertension could all be exacerbated by signals from the inflamed hypothalamus. \u00a0In agreement with Cacadas, they identified GnRH (gonadotropin-releasing hormone) as one downstream target, and were able to delay aging simply by treatment with this one hormone. \u00a0IKK-\u00df is produced by microglial cells in the hypothalamus of old mice but not young mice. \u00a0Genetically modified IKK-\u00df knock-out mice developed normally but lived longer and retained youthful brain performance later in life.<\/p>\n<p>In the <a href=\"https:\/\/www.nature.com\/nature\/journal\/v548\/n7665\/pdf\/nature23282.pdf#references\">new paper<\/a>, Cai\u2019s group identified micro-RNAs, secreted by the aging hypothalamus and circulating through the spinal fluid, that contribute to aging. \u00a0A small number of stem cells in the hypothalamus were found to keep the mouse young, in part by secreting these micro-RNAs. \u00a0Mice in which these stem cells were ablated had foreshortened life spans; old mice that were treated with implants of hypothalamic stem cells from younger mice were rejuvenated and lived longer. \u00a0A class of neuroendocrine stem cells from the third ventricle wall of the hypothalamus (nt-NSC\u2019s) was identified as having a powerful programmatic effect on aging. \u00a0These cells are normally lost with age, and restoring these cells alone in old mice extended their life spans.<\/p>\n<p><a href=\"https:\/\/en.wikipedia.org\/wiki\/Exosome_(vesicle)\">Exosomes<\/a> are little packets of signal chemicals. Micro-RNAs from stem cells in the hypothalamus are collected into exosomes and shipped down through the spinal fluid. \u00a0These exosomes seem to constitute a feedback loop. \u00a0On the one hand, they are generated by the hypothalamic stem cells. \u00a0On the other hand, they play a role in keeping these same cells young, and producing more exosomes.<\/p>\n<p>Life extension of about 12% was impressive given that there was just one intervention when the mice were more than 1\u00bd years old, but of course it\u2019s not what we would hope for if the master aging clock were reset. \u00a0For really large increases in lifespan, we will probably need to reset two or even three of the clocks at once.<\/p>\n<p>&nbsp;<\/p>\n<p><b>The Bottom Line<\/b><\/p>\n<p>The reason the body has multiple, redundant aging clocks is to assure that natural selection can\u2019t defeat aging by throwing a single switch. \u00a0That means the clocks must be at least somewhat independent. \u00a0Nevertheless, I judge it is likely that there is some crosstalk among clocks, because that\u2019s how biology usually works. \u00a0To effect rejuvenation, we will have to address all aging clocks, but we see some benefit from resetting even one, and expect more significant benefit from resetting two or more.<\/p>\n<p>The most challenging target is the epigenetic clock,built on a homeostasis of transcription and signaling among hundreds of hormones that each affect levels of the others. \u00a0Reverse engineering this tangle will be a bear.<\/p>\n<p>The idea of a centralized aging clock in the hypothalamus seems far more accessible, and is promising for the medium term. \u00a0Still, it does not suggest immediate application to remedies. \u00a0The hypothalamus is deep in the brain, and you and I might be reluctant to accept a treatment that required drilling through the skull. \u00a0A treatment based on circulating proteins and RNAs from the hypothalamus would be less invasive, but even that might have to be intravenous, and include some chemistry for penetrating the blood-brain barrier. \u00a0RNA exosomes seem to be our best opportunity<\/p>\n<p>As Cavadas\u2019s group has already pointed out, it is inflammation in the hypothalamus that is amplified by signaling to become most damaging to the entire body. \u00a0This raises the interesting question: could it be that the modest anti-aging power of NSAIDs is entirely due to their action within the brain? \u00a0In other words, maybe \u201cinflammaging\u201d is largely localized to the hypothalamus.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Last week, a new study came out fingering the hypothalamus as locus of a clock that modulates aging. \u00a0This encourages those of us who entertain the most optimistic scenarios for anti-aging medicine. \u00a0Could it be that altering the biochemistry of one tiny control center might effect global rejuvenation? \u00a0 First some background\u2026. I have staked &#8230; <a title=\"Building the Case that Aging is Controlled from the Brain\" class=\"read-more\" href=\"https:\/\/scienceblog.com\/joshmitteldorf\/2017\/08\/07\/building-the-case-that-aging-is-controlled-from-the-brain\/\" aria-label=\"Read more about Building the Case that Aging is Controlled from the Brain\">Read more<\/a><\/p>\n","protected":false},"author":65,"featured_media":600,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":"","jetpack_post_was_ever_published":false},"categories":[1],"tags":[],"class_list":["post-599","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-uncategorized"],"yoast_head":"<!-- This site is optimized with the Yoast SEO Premium plugin v27.7 (Yoast SEO v27.7) - https:\/\/yoast.com\/product\/yoast-seo-premium-wordpress\/ -->\n<title>Building the Case that Aging is Controlled from the Brain - Josh Mitteldorf<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/scienceblog.com\/joshmitteldorf\/2017\/08\/07\/building-the-case-that-aging-is-controlled-from-the-brain\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Building the Case that Aging is Controlled from the Brain\" \/>\n<meta property=\"og:description\" content=\"Last week, a new study came out fingering the hypothalamus as locus of a clock that modulates aging. \u00a0This encourages those of us who entertain the most optimistic scenarios for anti-aging medicine. \u00a0Could it be that altering the biochemistry of one tiny control center might effect global rejuvenation? \u00a0 First some background\u2026. 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The surprising fact that our bodies are genetically programmed to age and to die offers an enormous opportunity for medical intervention. It may be that therapies to slow the progress of aging need not repair or regenerate anything, but only need to interfere with an existing program of self-destruction. Mitteldorf has taught a weekly yoga class for thirty years. He is an advocate for vigorous self care, including exercise, meditation and caloric restriction. After earning a PhD in astrophysicist, Mitteldorf moved to evolutionary biology as a primary field in 1996. He has taught at Harvard, Berkeley, Bryn Mawr, LaSalle and Temple University. He is presently affiliated with MIT as a visiting scholar. In private life, Mitteldorf is an advocate for election integrity as well as public health. He is an avid amateur musician, playing piano in chamber groups, French horn in community orchestras. His two daughters are among the first children adopted from China in the mid-1980s. Much to the surprise of evolutionary biologists, genetic experiments indicate that aging has been selected as an adaptation for its own sake. This poses a conundrum: the impact of aging on individual fitness is wholly negative, so aging must be regarded as a kind of evolutionary altruism. Unlike other forms of evolutionary altruism, aging offers benefits to the community that are weak, and not well focussed on near kin of the altruist. This makes the mechanism challenging to understand and to model. more at http:\\\/\\\/mathforum.org\\\/~josh\",\"sameAs\":[\"http:\\\/\\\/AgingAdvice.org\"],\"url\":\"https:\\\/\\\/scienceblog.com\\\/joshmitteldorf\\\/author\\\/joshmitteldorf\\\/\"}]}<\/script>\n<!-- \/ Yoast SEO Premium plugin. -->","yoast_head_json":{"title":"Building the Case that Aging is Controlled from the Brain - Josh Mitteldorf","robots":{"index":"index","follow":"follow","max-snippet":"max-snippet:-1","max-image-preview":"max-image-preview:large","max-video-preview":"max-video-preview:-1"},"canonical":"https:\/\/scienceblog.com\/joshmitteldorf\/2017\/08\/07\/building-the-case-that-aging-is-controlled-from-the-brain\/","og_locale":"en_US","og_type":"article","og_title":"Building the Case that Aging is Controlled from the Brain","og_description":"Last week, a new study came out fingering the hypothalamus as locus of a clock that modulates aging. \u00a0This encourages those of us who entertain the most optimistic scenarios for anti-aging medicine. \u00a0Could it be that altering the biochemistry of one tiny control center might effect global rejuvenation? \u00a0 First some background\u2026. 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