Is there an Aging Clock in the Hypothalamus?

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

I believe that aging is centrally controlled on a schedule.  Most researchers don’t believe that yet, but everyone accepts broad evidence that the timing of aging can be modified by central signals.  All the signals about hunger and stress and sex, etc, that affect aging must somehow be integrated into a decision.  It seems logical that this happens in the brain, and messages are passed to the body through chemical signals.  This is a process that is just beginning to be understood, but the biochemists who study regulation to the brain are looking to the hypothalamus as a probable center for time-keeping, decision-making, and broadcast of chemical signals that regulate aging.  We may hope that if the hypothalamus thinks we are young, then it will make us young.  (I discussed some background in this space 2 years ago.)

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.  [Rando, Blagosklonny, Mitteldorf, Magalhaes, Johnson]

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

source:  http://antranik.org/the-diencephalon

source: http://antranik.org/the-diencephalon

 

Orexin aka Hypocretin

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

Orexin is produced in a tiny region of the hypothalamus.

Drugs that block orexin have been developed recently as aids in overcoming addiction.  There are also applications for insomnia.  Orexin makes you awake and alert; blocking orexin helps facilitate sleep.

The “rate of living” hypothesis is an old, discredited theory–such ideas take a long time to die.  You might expect that orexin speeds you up, so it shortens life span.  The opposite is true.  Orexin speeds you up, and it increases life span.

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.  Mice that have no leptin (ob/ob) are found to have lowered levels of orexin.  They are obese and have shorter life spans. This and other evidence suggests that orexin is beneficial for maintaining insulin sensitivity, avoiding diabetes.

Loss of insulin sensitivity is a core mechanism of human aging.  We have less orexin as we age.  Orexin helps maintain insulin sensitivity.  Putting these pieces together, we have a plausible rationale for looking for anti-aging benefits from increased orexin expression.

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]

Orexin is not a large protein molecule, but large enough that it won’t survive digestion.  You can’t 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.

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]

NFκB is a hormone that promotes inflammation and is widely regarded as pro-aging.  In experiments with mice, NFκB inhibition extended life span by blocking GnRH in the hypothalamus [ref].

 

Neuropeptide Y

Note: I regret that this blog post is turning into alphabet soup.  Biochemistry 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’re hoping for.  I’m still hoping that aging turns out to have a basis that is manageably simple, with a few chemicals at the control center.  But perhaps we have to map a good deal of the biochemical web before we can identify the controlling nodes.

Neuropeptide Y is another small neurotransmitter protein, in the news this spring because of work from the laboratory of Claudia Cavadas in Coimbra, Portugal.  Autophagy is the recycling and renewal of large molecules in a cell that become degraded over time if they are not refreshed.  Autophagy is dialed down as we age, leading to aging cells and an aging body.  The Cavadas group has identified Neuropeptide Y (NPY) as a signal that comes from the hypothalamus, and tells cells to keep autophagy up.  We have less NPY as we age, and people with Alzheimer’s and Parkinson’s diseases have less NPY.  The Cavadas team notes that NPY in the hypothalamus is increased in rats that are living longer due to calorie restriction.  The new experiments added NPY to cell cultures, and found that NPY promotes autophagy in vitro.  They went on to the more difficult experiment in live mice, using gene therapy to increase NPY in neurons only.  This caused the mice to eat more, so they were put on a feeding regimen where they ate no more than control mice that didn’t have extra NPY.  The 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.

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]

Previous experiments 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.  NPY is also associated with renewal of the immune system.

The Bottom Line

This line of thinking is still largely theoretical.  The only practical recommendation is to take melatonin at bedtime after age 50.  But it may be that the hypothalamus is ground zero for signals that tell the body how old it is.  (Here is a recent editorial from Buck Institute on the subject of neuropeptides and aging.)  I 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.

11 thoughts on “Is there an Aging Clock in the Hypothalamus?

  1. The big question becomes whether or not there is something that can be done to convince the Hypothalamus that it is younger than it actually is.

    Otherwise, the only other thing may be Neuropeptide Y and Orexin – is there any way to get it delivered in such a way that it would survive into the digestive track? I have heard of capsules for probiotics (the ones that are actually useful, which most are not) have to have their capsules designed in such a manner that the bacteria in the probiotic will survive the acidity of the stomach to get to the intestines.

  2. Josh says…
    “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. [Rando, Blagosklonny, Mitteldorf, Magalhaes, Johnson]”

    the author names above are links to papers mostly published in 2012 and one in 2006,,that mostly lk about DNA methylatiobn
    ,,but do you want know where the idea first came from? from a 1998 paper…….read the first sentence…..and then note how epigentic loss of DNA methylation is idenified as the timer of aging….I gave this paper to Magalhaes at a 2000 aging confrence in Spa belgium and to him to carry on with my work as I was going to doother things….I think he finally got it!!

    Med Hypotheses. 1998 Sep;51(3):179-221.
    The evolution of aging: a new approach to an old problem of biology.
    Bowles JT1.
    Author information
    Abstract
    Most gerontologists believe aging did not evolve, is accidental, and is unrelated to development. The opposite viewpoint is most likely correct. Genetic drift occurs in finite populations and leads to homozygosity in multiple-alleled traits. Episodic selection events will alter random drift towards homozygosity in alleles that increase fitness with respect to the selection event. Aging increases population turnover, which accelerates the benefit of genetic drift. This advantage of aging led to the evolution of aging systems (ASs). Periodic predation was the most prevalent episodic selection pressure in evolution. Effective defenses to predation that allow exceptionally long lifespans to evolve are shells, extreme intelligence, isolation, and flight. Without episodic predation, aging provides no advantage and aging systems will be deactivated to increase reproductive potential in unrestricted environments. The periodic advantage of aging led to the periodic evolution of aging systems. Newer aging systems co-opted and added to prior aging systems. Aging organisms should have one dominant, aging system that co-opts vestiges of earlier-evolved systems as well as vestiges of prior systems. In human evolution, aging systems chronologically emerged as follows: telomere shortening, mitochondrial aging, mutation accumulation, senescent gene expression (AS#4), targeted somatic tissue apoptotic-atrophy (AS#5), and female reproductive tissue apoptotic-atrophy (AS#6). During famine or drought, to avoid extinction, reproduction is curtailed and aging is slowed or somewhat reversed to postpone or reverse reproductive senescence. AS#4-AS#6 are gradual and reversible aging systems. The life-extending/rejuvenating effects of caloric restriction support the idea of aging reversibility. Development and aging are timed by the gradual loss of cytosine methylation in the genome. Methylated cytosines (5mC) inhibit gene transcription, and deoxyribonucleic acid (DNA) cleavage by restriction enzymes. Cleavage inhibition prevents apoptosis, which requires DNA fragmentation. Free radicals catalyze the demethylation of 5mC while antioxidants catalyze the remethylation of cytosine by altering the activity of DNA methyltransferases. Hormones act as either surrogate free radicals by stimulating the cyclic adenosine monophosphate (cAMP) pathway or as surrogate antioxidants through cyclic guanosine monophosphate (cGMP) pathway stimulation. Access to DNA containing 5mC inhibited developmental and aging genes and restriction sites is allowed by DNA helicase strand separation. Tightly wound DNA does not allow this access. The DNA helicase generates free radicals during strand separation; hormones either amplify or counteract this effect. Caloric restriction slows or reverses the aging process by increasing melatonin levels, which suppresses reproductive and free radical hormones, while increasing antioxidant hormone levels. Cell apoptosis during CR leads to somatic wasting and a release of DNA, which increases bioavailable cGMP. The rapid aging diseases of progeria, the three diseases: (xeroderma pigmentosum (XP), Cockayne syndrome(CS), and ataxia telangiectasia (AT)), and Werner’s syndrome are related to or caused by defects in three separate DNA helicases. The rapid aging diseases caused by mitochondrial malfunctions mirror those seen in XP, CS, and AT. Comparing these diseases allows for assignment of the different symptoms of aging to their respective aging systems. Follicle-stimulating hormone (FSH) demethylates the genes of AS#4, luteinizing hormone (LH) of AS#5, and estrogen of AS#6 while cortisol may act cooperatively with FSH and LH, and 5-alpha dihydrotestosterone (DHT) with FSH in these role. The Werner’s DNA helicase links timing of the age of puberty, menopause, and maximum lifespan in one mechanism. Telomerase is under hormonal control. Most cancers likely result from malfunctions in the programmed apoptosis of AS#5 and AS#6. The Hayflick limit is reached primarily through loss of cytosine methylation of genes that inhibit replication. Men suffer the diseases of AS#4 at a higher rate than women who suffer from AS#5 more often. Adult mammal cloning suggests aging-related cellular demethylation, and thus aging, is reversible. This theory suggests that the protective effect of smoking and ibuprofen for Alzheimer’s disease is caused through LH suppression.

    • Nice abstract. Interesting though how much he tries to push free radicals as a wildcard for probably unknown processes. Maybe this was the only way he could have it published that time?

      Role of DNA helicases in aging is new to me. Is it proven?

      • I agree with the assertion that Telomerase is controlled to a considerable extent by Estrogen. I trawled through dozens of papers and found a lot of evidence to support Androgens and Estrogens in particular can up-regulate and control Telomerase.

        The question I have now is assuming Androgens are a major player in the regulation of Telomerase would intervention at the Telomeres as Dr Michael Fossel is suggesting allow us to leapfrog the complexity of balancing hormones and revert the phenotype by extending the Telomeres as he suggests?

        • Josh,

          Do you think it is worth exploring the Inhibition of NK-FB in the brain as a combined approach for aging with say TERT therapy on a systemic level?

          I know HDW from Longecity is very keen on NF-KB perhaps we could inhibit it or GnRH ?

          • Sure, it sounds good to me. I don’t have any funding to allocate, so it’s easy for me to be in favor of all of it. But I agree with you this is a particularly promising approach.

          • Melatonion suppresses LH and FSH and thus can be uased as birth control (and anti aging)
            Maybe it does this by suppressing GnRH … Maybe Ill look into it

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