Aging and the Hypothalmus

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]



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.


This post originally appeared in Josh’s Aging Matters blog here. Republished with permission.