Last week, a new study came out fingering the hypothalamus as locus of a clock that modulates aging.  This encourages those of us who entertain the most optimistic scenarios for anti-aging medicine.  Could it be that altering the biochemistry of one tiny control center might effect global rejuvenation?  

First some background….

I have staked my career on the interpretation that aging unfolds under the body’s full control.  Even 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

I believe that aging is governed by an internal biological clock, or several semi-independent and redundant clocks.  There are

  • A telomere clock, counting cell divisions on a flexible schedule, eventually producing cells with short-telomeres that poison us.
  • The thymus, crucial training ground for our white blood cells, shrinks through a lifetime.
  • An epigenetic clock alters gene expression over time in directions that give rise to self-destruction.
  • A neuroendocrine clock in the hypothalamus
  • Perhaps other clocks, yet to be identified.

 

A dream is to be able to reset the hands of the clock.  If we’re 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.  Most 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 “youth” in the body’s native biochemical tongue.

Some of these clocks are more accessible and easier to manipulate than others.  The 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.  This 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.  (For several years, the Mike and Irina Conboy have 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.)

At the other end of the spectrum, the hypothalamic clock presents the most optimistic scenario.  It is tightly localized in a tiny region of the brain, and might be relatively easy to manipulate, with consequences that rejuvenate the entire body.  The hypothalamic clock hypothesis is an attractive target for research because, if correct, it will offer direct and straightforward control over the body’s metabolic age.

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.  There has to be a clock for development that determines when growth surges and stops, when sex hormones turn on and, if it’s not too great a stretch, when fertility ends and menopause unfolds.

The clock that governs growth and development has yet to be elucidated—a major metabolic mystery by my lights.  The 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.

Is the life history clock linked to the circadian clock?  Maybe the body just counts days to tell how old it is?  This possibility was eliminated, at least for flies, using experiments with cycles of light and dark that were consistently longer or shorter than 24 hours.  Flies 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,  In fact, deviation from 24 hours in either direction shorten the fly’s lifespan [2005].  

But this study suggests the short-term clock and the long-term clock may be linked in a way that is less straightforward.  Melatonin may be another reason to expect a connection.  Melatonin is the body’s cue for sleep, and Russian studies have documented a role for melatonin in aging.  A third motivation comes from the fact that aging disrupts sleep cycles, and (in a downward spiral) disrupted sleep cycles are also a risk factor for mortality and diseases of old age.

Cells seem to have their own, built-in daily rhythms.  I want to say “transcriptional rhythms”, adding the idea that gene transcription is the locus of control; however, red blood cells are the counterexample—they exhibit daily cycles, even though they have no DNA to transcribe [2011].  Individual cycles are designed to be 24 hours, but they would soon drift out of phase with day and night if they weren’t centrally coordinated.  The reference clock that keeps the others in line is in the SCN, the suprachiasmatic nucleus, a handful of nerve cells in a neuroendocrine part of the brain called the hypothalamus.

Think of a million pendulums that are all tuned to swing with a period of 24 hours.  All 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.  The 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.  The SCN is upstream of the pineal gland, and supplies the signal that tells the pineal gland when it’s time to make melatonin.  The natural resonances of individual cells become entrained in a body-wide response.

 

What does all this have to do with aging?

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.  For 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.  Transplanting a SCN from young hamsters into old hamsters cut their mortality rate by more than half, and extended their life expectancies by 4 months [1998].

I have written in this column [one, two] about research from the laboratory of Claudia Cavadas (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.  They have emphasized the role of TGFß binding to ALK5 and of the neurotransmitter NPY.  We 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.  Blocking inflammation in the hypothalamus is a promising anti-aging strategy.

New Paper on micro RNAs from the Hypothalamus

Along with Cavadas, Dongshen Cai (Einstein College of Medicine) has been a leader in exploring neuroendocrine control of aging that originates in the hypothalamus.  Several years ago, Cai’s group demonstrated that aging could be slowed in mice by inhibiting the inflammatory cytokine NF-kB and the related cytokine IKK-ß just in one tiny area of the brain, the hypothalamus.  “In conclusion, the hypothalamus has a programmatic role in ageing development via immune–neuroendocrine integration…”  They 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.  In 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.  IKK-ß is produced by microglial cells in the hypothalamus of old mice but not young mice.  Genetically modified IKK-ß knock-out mice developed normally but lived longer and retained youthful brain performance later in life.

In the new paper, Cai’s group identified micro-RNAs, secreted by the aging hypothalamus and circulating through the spinal fluid, that contribute to aging.  A small number of stem cells in the hypothalamus were found to keep the mouse young, in part by secreting these micro-RNAs.  Mice 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.  A class of neuroendocrine stem cells from the third ventricle wall of the hypothalamus (nt-NSC’s) was identified as having a powerful programmatic effect on aging.  These cells are normally lost with age, and restoring these cells alone in old mice extended their life spans.

Exosomes 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.  These exosomes seem to constitute a feedback loop.  On the one hand, they are generated by the hypothalamic stem cells.  On the other hand, they play a role in keeping these same cells young, and producing more exosomes.

Life extension of about 12% was impressive given that there was just one intervention when the mice were more than 1½ years old, but of course it’s not what we would hope for if the master aging clock were reset.  For really large increases in lifespan, we will probably need to reset two or even three of the clocks at once.

 

The Bottom Line

The reason the body has multiple, redundant aging clocks is to assure that natural selection can’t defeat aging by throwing a single switch.  That means the clocks must be at least somewhat independent.  Nevertheless, I judge it is likely that there is some crosstalk among clocks, because that’s how biology usually works.  To 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.

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.  Reverse engineering this tangle will be a bear.

The idea of a centralized aging clock in the hypothalamus seems far more accessible, and is promising for the medium term.  Still, it does not suggest immediate application to remedies.  The hypothalamus is deep in the brain, and you and I might be reluctant to accept a treatment that required drilling through the skull.  A 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.  RNA exosomes seem to be our best opportunity

As Cavadas’s group has already pointed out, it is inflammation in the hypothalamus that is amplified by signaling to become most damaging to the entire body.  This raises the interesting question: could it be that the modest anti-aging power of NSAIDs is entirely due to their action within the brain?  In other words, maybe “inflammaging” is largely localized to the hypothalamus.