{"id":386,"date":"2015-06-12T20:56:33","date_gmt":"2015-06-12T20:56:33","guid":{"rendered":"http:\/\/joshmitteldorf.peachpuff-wolverine-566518.hostingersite.com\/?p=386"},"modified":"2015-06-12T20:56:33","modified_gmt":"2015-06-12T20:56:33","slug":"is-there-an-aging-clock-in-the-hypothalamus","status":"publish","type":"post","link":"https:\/\/scienceblog.com\/joshmitteldorf\/2015\/06\/12\/is-there-an-aging-clock-in-the-hypothalamus\/","title":{"rendered":"Is there an Aging Clock in the Hypothalamus?"},"content":{"rendered":"

The brain does its work with electrical<\/span> signals through a network of neurons. \u00a0The information is passed to every cell in the body with chemical<\/span> signals, hormones, RNAs and proteins that are dissolved in the blood. \u00a0The interface between the electrical and the chemical networks is a tiny region in the middle of the brain, the hypothalamus. \u00a0<\/em><\/p>\n

I believe that aging is centrally controlled on a schedule. \u00a0Most researchers don\u2019t believe that yet, but everyone accepts broad evidence that the timing of aging can be modified by central signals. \u00a0All the signals about hunger and stress and sex, etc, that affect aging must somehow be integrated into a decision. \u00a0It seems logical that this happens in the brain, and messages are passed to the body through chemical signals. \u00a0This is a process that is just beginning to be understood<\/a>, but the biochemists who study regulation to the brain are looking to the hypothalamus<\/a> as a probable center for time-keeping, decision-making, and broadcast of chemical signals that regulate aging. \u00a0We may hope that if the hypothalamus thinks we are young, then it will make us young. \u00a0(I discussed some background in this space 2 years ago<\/a>.)<\/em><\/p>\n

The idea is emerging in recent years that aging is controlled by the same epigenetic clock as development, continued through the life time after growth has come to an end. \u00a0[Rando<\/a>, Blagosklonny<\/a>, Mitteldorf<\/a>, Magalhaes<\/a>, Johnson<\/a>]<\/p>\n

Growth and sexual maturity are controlled by secretions of the hypothalamus and the pituitary, which is just below the hypothalamus [background<\/a>]. \u00a0Sex hormones themselves come from the genitals, but they respond to signals from the hypothalamus, in the form of GnRH, gonadotropin-releasing hormone<\/a>. \u00a0(Timing for sleep\/wake cycles is controlled through melatonin<\/a> from the pineal body, which is part of the epithalamus, just behind the hypothalamus.) \u00a0[basics<\/a>]<\/p>\n

\"source:<\/a>
source: http:\/\/antranik.org\/the-diencephalon<\/figcaption><\/figure>\n

 <\/p>\n

Orexin aka Hypocretin<\/b><\/p>\n

Orexin<\/a> (also called hypocretin) is a neurotransmitter protein, just 33 BP long, associated with wakefulness, alertness, appetite and cravings. \u00a0Mice lacking the gene for orexin display narcolepsy. \u00a0They are continually falling asleep, only to waken a few moments later.<\/p>\n

Orexin is produced in a tiny region of the hypothalamus.<\/p>\n

Drugs that block orexin have been developed recently as aids in overcoming addiction. \u00a0There are also applications for insomnia. \u00a0Orexin makes you awake and alert; blocking orexin helps facilitate sleep.<\/p>\n

The \u201crate of living\u201d hypothesis is an old, discredited theory–such ideas take a long time to die. \u00a0You might expect that orexin speeds you up, so it shortens life span. \u00a0The opposite is true. \u00a0Orexin speeds you up, and it increases<\/i><\/b> life span.<\/p>\n

Mice that are genetically modified to have no orexin tend to obesity–again this is counterintuitive, if you think of orexin as an appetite hormone. \u00a0Mice that have no leptin (ob\/ob) are found to have lowered levels of orexin. \u00a0They are obese and have shorter life spans. This and other evidence suggests that orexin is beneficial for maintaining insulin sensitivity, avoiding diabetes.<\/p>\n

Loss of insulin sensitivity is a core mechanism of human aging. \u00a0We have less orexin as we age. \u00a0Orexin helps maintain insulin sensitivity. \u00a0Putting these pieces together, we have a plausible rationale for looking for anti-aging benefits from increased orexin expression.<\/p>\n

Recent evidence indicates that orexin efficiently protects against the development of peripheral insulin resistance induced by ageing or high-fat feeding in mice. In particular, the orexin receptor-2 signalling appears to confer resistance to diet-induced obesity and insulin insensitivity by improving leptin sensitivity. [2009<\/a>]<\/em><\/p><\/blockquote>\n

Orexin is not a large protein molecule, but large enough that it won’t survive digestion. \u00a0You can\u2019t eat it because digestion efficiently destroys proteins, but there is a nasal spray with orexin that is being explored in experiments with animals and humans.<\/p>\n

Mice with extra SIRT1 in the brain live longer, and the action of SIRT1 has been traced to the hypothalamus, and specifically to a stronger role for orexin. [ref<\/a>]<\/p>\n

NF\u03baB<\/a> is a hormone that promotes inflammation and is widely regarded as pro-aging. \u00a0In experiments with mice, NF\u03baB inhibition extended life span by blocking GnRH in the hypothalamus [ref<\/a>].<\/p>\n

 <\/p>\n

Neuropeptide Y<\/b><\/p>\n

Note: I regret that this blog post is turning into alphabet soup. \u00a0Biochemistry is not my native tongue, and I tend to think that mapping the network of cross-relationships among hundreds or thousands of native hormones is not likely to lead to the silver bullet that we\u2019re hoping for. \u00a0I’m still hoping that aging turns out to have a basis that is manageably simple, with a few chemicals at the control center. \u00a0But perhaps we have to map a good deal of the biochemical web before we can identify the controlling nodes.<\/i><\/p>\n

Neuropeptide Y<\/a> is another small neurotransmitter protein,\u00a0in the news this spring\u00a0because of work from\u00a0the laboratory of Claudia Cavadas<\/a> in Coimbra, Portugal. \u00a0Autophagy<\/a> is the recycling and renewal of large molecules in a cell that become degraded over time if they are not refreshed. \u00a0Autophagy is dialed down as we age, leading to aging cells and an aging body. \u00a0The Cavadas group has identified Neuropeptide Y (NPY) as a signal that comes from the hypothalamus, and tells cells to keep autophagy up. \u00a0We have less NPY as we age, and people with Alzheimer\u2019s and Parkinson\u2019s diseases have less NPY. \u00a0The Cavadas team notes that NPY in the hypothalamus is increased in rats that are living longer due to calorie restriction. \u00a0The new experiments added NPY to cell cultures, and found that NPY promotes autophagy in vitro<\/i>. \u00a0They went on to the more difficult experiment in live mice, using gene therapy to increase NPY in neurons only. \u00a0This caused the mice to eat more, so they were put on a feeding regimen where they ate no more than control mice that didn\u2019t have extra NPY. \u00a0The treatment successfully upgraded autophagy, but left open the question of how much of this was due to caloric restriction and how much to the NPY itself.<\/p>\n

Autophagy impairment is a major hallmark of aging, and any intervention that enhances autophagy is of potential interest to delay aging. However, itwas described that the hypothalamus is a brain area with a key role on whole-body aging. In the present study, we show that an endogenous molecule produced by the hypothalamus, the neuropeptide Y (NPY), stimulates autophagy in rodent hypothalamus. Because both hypothalamic autophagy and NPY levels decrease with age, a better understanding of hypothalamic neuronal autophagy regulation by NPY may provide new putative therapeutic strategies to ameliorate agerelated deteriorations and delay aging. [Source<\/a>]<\/em><\/p><\/blockquote>\n

Previous experiments<\/a> with rats had shown that whole-body overexpression of NPY leads both to 10% longer life span and better blood pressure control, without weight gain. \u00a0NPY is also associated with renewal of the immune system<\/a>.<\/p>\n

The Bottom Line<\/b><\/p>\n

This line of thinking is still largely theoretical. \u00a0The only practical recommendation is to take melatonin at bedtime<\/a> after age 50. \u00a0But it may be that the hypothalamus is ground zero for signals that tell the body how old it is. \u00a0(Here is a recent editorial<\/a> from Buck Institute on the subject of neuropeptides and aging.) \u00a0I believe that the hypothalamus and its secretions are a promising area for new research, and that, over the next few years, basic findings will lead to the most powerful interventions to change the course of aging.<\/p>\n","protected":false},"excerpt":{"rendered":"

The brain does its work with electrical signals through a network of neurons. \u00a0The information is passed to every cell in the body with chemical signals, hormones, RNAs and proteins that are dissolved in the blood. \u00a0The interface between the electrical and the chemical networks is a tiny region in the middle of the brain, … Read more<\/a><\/p>\n","protected":false},"author":65,"featured_media":0,"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-386","post","type-post","status-publish","format-standard","hentry","category-uncategorized"],"yoast_head":"\nIs there an Aging Clock in the Hypothalamus? - 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\/2015\/06\/12\/is-there-an-aging-clock-in-the-hypothalamus\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Is there an Aging Clock in the Hypothalamus?\" \/>\n<meta property=\"og:description\" content=\"The brain does its work with electrical signals through a network of neurons. \u00a0The information is passed to every cell in the body with chemical signals, hormones, RNAs and proteins that are dissolved in the blood. \u00a0The interface between the electrical and the chemical networks is a tiny region in the middle of the brain, ... 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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":"Is there an Aging Clock in the Hypothalamus? - 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\/2015\/06\/12\/is-there-an-aging-clock-in-the-hypothalamus\/","og_locale":"en_US","og_type":"article","og_title":"Is there an Aging Clock in the Hypothalamus?","og_description":"The brain does its work with electrical signals through a network of neurons. \u00a0The information is passed to every cell in the body with chemical signals, hormones, RNAs and proteins that are dissolved in the blood. \u00a0The interface between the electrical and the chemical networks is a tiny region in the middle of the brain, ... 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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\/"}]}},"jetpack_featured_media_url":"","jetpack_shortlink":"https:\/\/wp.me\/pgtN8h-6e","jetpack_sharing_enabled":true,"_links":{"self":[{"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/posts\/386","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/users\/65"}],"replies":[{"embeddable":true,"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/comments?post=386"}],"version-history":[{"count":0,"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/posts\/386\/revisions"}],"wp:attachment":[{"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/media?parent=386"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/categories?post=386"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/scienceblog.com\/joshmitteldorf\/wp-json\/wp\/v2\/tags?post=386"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}