Building the Case that Aging is Controlled from the Brain

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.


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115 thoughts on “Building the Case that Aging is Controlled from the Brain”

  1. I would rank this as my favorite post – top form – every word from start to finish. Gives a great perspective about biological clocks. On the mark on every deduction made. Loved it! George Church may make some significant contribution towards the most challenging clock – rewriting the epigenetic clock – a faint hope that we see some success in our life time.

    Reply
  2. Well written Josh ! thank you. I have 3 comments.
    1 : Micro-rna’s seem to be the smoking gun of aging. So now the aim should be to work out how to stop it ‘firing’.
    2 If “the body has multiple, redundant aging clocks is to assure that natural selection can’t defeat aging by throwing a single switch”, how is aging so slowly in species like the Galapogos Tortises or a tree like the Californian Red wood ?
    Here it seems that all of the switches have been altered and the result is extreme longevity.
    3 : Your remark at the end about the modest anti aging power of NSAIDs seems a bit of a teaser. Can you elaborate a bit on this ?

    Reply
    • Great article! I believe Josh was probably first exposed to the idea of multiple aging “clocks:” by reading my 1998 paper about aging>>>>at the time I called them aging systems and tried to identify 6 of them by mainly comparing the various rapid aging diseases that show segments of aging but not the full spectrum of aging symptoms.. I think this approach will still prove t\o be instructive>>here are hilights from gthe table in that 1998 paper that might interest Josh more these days with his interest in aging clocks>>>>

      Defective Lamin A protein Progeria=Senescent Gene Expression: Controlled by hormones FSH & DHT, seen in men at higher rate. Co-opts Telomere shortening symptoms

      Aging symptoms seen in Progeria only.

      Coxa Valga & necrosis of head of femur
      Dysplastic osteoporosis

      Aging Symptoms of progeria also seen in Werner’s Syndorme:

      Atherosclerosis
      Hypertension
      Gray Hair
      Alopecia
      Calcification of Heart Valves
      Laryngeal Atrophy
      Loss of subcutaneous tissue
      Hypermelanosis of Skin
      Hypogonadism (defect of development?)

      Aging Driven by Mitochondrial directed Apoptosis, controlled by hormones LH & hCG , seen in women at a higher rate
      Aging symptoms seen in these rapid aging mitochondrial diseases>
      Mitochondrial Myopathy (MM), NARP (N), CPEO (CP), MELAS (ME), MERRF (MR) , KSS (K), Dystonia (D), Leigh’s Syndrome (LS)

      Symptoms of mitochondrial aging also seen in Werner’s syndrome
      Muscle Wasting-MM, N
      Neuronal Degeneration/Brain Atrophy-CP, ME, MR, K
      Basal Ganglion Calcification – D, LS
      Cataracts-K
      Diabetes-K
      Alzheimer’s Disease-mitochondrial induced

      Nuclear DNA driven apoptosis related aging /also controlled byhormones LH & hCGLH/hCG driven, seen in women at a higher rate and seen accelerated in these diseases that exhibit excessive apoptosis/tissue atrophy and caused by defects in DNA replicating proteins that cause excess apoptosis >>
      Ataxia Telangiectasia (AT), Xeroderma Pigmentosum (XP), Cockayne Syndrome (CS).
      mitochondriual aging symptoms >>
      Hypogonadism -AT, XP (also seen in progeria and Werners Syndrome)
      Aging Symptoms for these diseases also seen in Werner’s syndrome
      Muscle Wasting-AT
      Neuronal Degeneration/Brain Atrophy -AT, XT
      Basal Ganglion Calcification – CS
      Cataracts-CS
      Diabetes-AT
      Alzheimer’s Disease-XP
      Poor Healing -XP
      Skin Ulcers -XP
      Thymic Atrophy-AT
      Scaly Skin-XP
      Somatic Cancers-XP,AT
      Lipofuscin Accumulation-CS,XP
      Arthritis-AT
      Peripheral Osteoporosis-CS

      And Finally the ULTIMATE AGING SYSTEM that coopts all the others>>
      Werner’s Syndrome caused by a defective helicase protein that also serves as an aging gene repressor (much like Lamin A protein in progeria)
      estrogen/DHT driven, seen in women at higher rate coopts all the prior aging systems from progeria to mitochondrial driven apoptosis to nuclear DNA driven apoptosis>>

      Symptoms of Werner’s Syndorme co-opted from progeria
      Atherosclerosis-WS
      Hypertension-WS
      Gray Hair-WS
      Alopecia-WS
      Calc. of Heart Valves-WS
      Laryngeal Atrophy-WS
      Loss of subcut. tissue-WS
      Hypermelanosis of Skin-WS
      Hypogonadism -WS, BS

      Symptoms of Werner’s Syndorme coopted from mitoch. driven apoptosis

      Muscle Wasting-WS
      Neuronal Degeneration, Brain Atrophy -WS
      Basal Ganglion Calcification -WS
      Cataracts-WS
      Diabetes-BS, WS
      Alzheimer’s Disease-WS

      Symptoms of Werner’s Syndorme coopted from nuclear DNA driven apoptosis
      Poor Healing -WS
      Skin Ulcers -WS
      Thymic Atrophy-BS, WS
      Scaly Skin-WS
      Somatic Cancers- BS, WS
      Lipofuscin Accumulation-WS
      Arthritis-WS
      Peripheral Osteoporosis-WS
      Symptoms unique to #6
      Menopause-WS
      Breast, Uterine, and Ovarian atrophy and cancer-WS
      Prostate atrophy-WS, hyperplasia-WS, and cancer-WS
      Depression-WS?

      so I know this all looks quite complicated but if you could see the table as it exists in my published paper you will notice that Werner’s syndrome is connected with and drives all the other aging clocks, and each subclock is associated with just a unique set up aging symptoms

      the sub clocks are elucidated by studying the rapid aging diseases of progeria (male-aging) does not include cancer or dementia), and mitochondrial driven apoptosis and nuclear DNA dricven apoptosis (female aging) includes cancer and dementia…

      The name of the paper with the table is The Evolution of Aging
      by Jeff T Bowles Med Hyp 1998 it might deserve another look

      one way to look at it is the DNJA is filled with various stciks of dynamaite wqith different length fuses>>the shortest fused stick kills you until you cna evolv e a longer fuise on that stick,,, then the next shortest fusaed stick gets you,,, etc etc…as .longevity keeps evolving all the fuses become tge same length

      in the end Im guessing the telomeres get you

      Reply
    • Tortoises never stop growing, so don’t have the issue of quiescent cells being driven to senescence by MTOR signaling, are also cold blooded, so have a very low metabolic rate. I expect, but do not know, that they also lose telomeres very slowly (or not at all, like mice).

      So perhaps they have defeated some of the clocks, but it is more likely they are just set to tick very slowly!

      Reply
  3. And what controls aging in yeast that don’t have a brain.
    From a medical perspective aging looks like the sum effect of different diseases. In my opinion, aging is not programmed, and not controlled. From an evolution viewpoint, programmed aging makes no sense as animals died soon enough from predators; there was no reason for all animals to carry with them a built in suicide pill just in case they didn’t get killed soon enough.
    Programmed aging and planned death only makes sense if one believes in God or some kind of intelligent master engineer. If one is looking for meaning,order and control. It makes no sense in a random universe.

    Alan Green, M.D.

    Reply
    • Sounds like ALan hasn’t done much thinking on this subject>>

      If you can say that programmed aging makes no sense>>>simply change programmed aging to menopause and go ahead with your argument that menopause is not programmed

      from an evolutionary perspective aging and menopause are the same thing!

      Reply
      • Now i dont mean to be pciking on Alan>>he is completely mainstream in his thinking and is no more wrong than Darwin or Dawkins on the idea of programmed aging>>
        let me propose the simple questions that if answered will get to the heart of the matter of whether aging is programmed or not>
        Almost eveyone agrees that menopause is programmed, right?
        If you can comed up with the evolutionary purpose of programmed menopause you will also have found the evolutionary purpose of programmed aging.l
        If menopause can be programmed, aging can be too.
        in fact they are both driven by the same hormone changes.
        This then leads to other questons like the evolutionary purpose of sex, there are quite a few animals that do not reproduce sexually like whiptail lizards, cave crickets, and the Brahma snake. It turns out I believe that if you can come up with the evolutionarty prupose of sex, you will also have uncovered the evolutionary purpose of programmed aging as well as menopause. Food for thought!

        Reply
      • Hi Jeff,
        Thanks for comment on menopause.
        Blagosklonny has very interesting paper, “Why men age faster but reproduce longer than women: mTOR and evolutionary perspectives.” 2010
        Paper has long discussion of menopause. Menopause is a very complex disease of aging, not programmed, but a quasi-programmed, which eventually burns out ovum.
        After you study paper, might have different idea about menopause.

        Reply
    • Alan – I have a great deal of respect for you, and I realize that programmed aging doesn’t square with traditional views of evolutionary biology. I thought a lot about this before concluding that the evidence for programmed aging was strong, and that evolutionary thinking would have to change to accommodate this reality. The story is in my book.

      Reply
  4. Great article! I believe Josh was probably first exposed to the idea of multiple aging “clocks:” by reading my 1998 paper about aging>>>>at the time I called them aging systems and tried to identify 6 of them by mainly comparing the various rapid aging diseases that show segments of aging but not the full spectrum of aging symptoms.. I think this approach will still prove t\o be instructive>>here are hilights from gthe table in that 1998 paper that might interest Josh more these days with his interest in aging clocks>>>>

    Defective Lamin A protein Progeria=Senescent Gene Expression: Controlled by hormones FSH & DHT, seen in men at higher rate. Co-opts Telomere shortening symptoms

    Aging symptoms seen in Progeria only.

    Coxa Valga & necrosis of head of femur
    Dysplastic osteoporosis

    Aging Symptoms of progeria also seen in Werner’s Syndorme:

    Atherosclerosis
    Hypertension
    Gray Hair
    Alopecia
    Calcification of Heart Valves
    Laryngeal Atrophy
    Loss of subcutaneous tissue
    Hypermelanosis of Skin
    Hypogonadism (defect of development?)

    Aging Driven by Mitochondrial directed Apoptosis, controlled by hormones LH & hCG , seen in women at a higher rate
    Aging symptoms seen in these rapid aging mitochondrial diseases>
    Mitochondrial Myopathy (MM), NARP (N), CPEO (CP), MELAS (ME), MERRF (MR) , KSS (K), Dystonia (D), Leigh’s Syndrome (LS)

    Symptoms of mitochondrial aging also seen in Werner’s syndrome
    Muscle Wasting-MM, N
    Neuronal Degeneration/Brain Atrophy-CP, ME, MR, K
    Basal Ganglion Calcification – D, LS
    Cataracts-K
    Diabetes-K
    Alzheimer’s Disease-mitochondrial induced

    Nuclear DNA driven apoptosis related aging /also controlled byhormones LH & hCGLH/hCG driven, seen in women at a higher rate and seen accelerated in these diseases that exhibit excessive apoptosis/tissue atrophy and caused by defects in DNA replicating proteins that cause excess apoptosis >>
    Ataxia Telangiectasia (AT), Xeroderma Pigmentosum (XP), Cockayne Syndrome (CS).
    mitochondriual aging symptoms >>
    Hypogonadism -AT, XP (also seen in progeria and Werners Syndrome)
    Aging Symptoms for these diseases also seen in Werner’s syndrome
    Muscle Wasting-AT
    Neuronal Degeneration/Brain Atrophy -AT, XT
    Basal Ganglion Calcification – CS
    Cataracts-CS
    Diabetes-AT
    Alzheimer’s Disease-XP
    Poor Healing -XP
    Skin Ulcers -XP
    Thymic Atrophy-AT
    Scaly Skin-XP
    Somatic Cancers-XP,AT
    Lipofuscin Accumulation-CS,XP
    Arthritis-AT
    Peripheral Osteoporosis-CS

    And Finally the ULTIMATE AGING SYSTEM that coopts all the others>>
    Werner’s Syndrome caused by a defective helicase protein that also serves as an aging gene repressor (much like Lamin A protein in progeria)
    estrogen/DHT driven, seen in women at higher rate coopts all the prior aging systems from progeria to mitochondrial driven apoptosis to nuclear DNA driven apoptosis>>

    Symptoms of Werner’s Syndorme co-opted from progeria
    Atherosclerosis-WS
    Hypertension-WS
    Gray Hair-WS
    Alopecia-WS
    Calc. of Heart Valves-WS
    Laryngeal Atrophy-WS
    Loss of subcut. tissue-WS
    Hypermelanosis of Skin-WS
    Hypogonadism -WS, BS

    Symptoms of Werner’s Syndorme coopted from mitoch. driven apoptosis

    Muscle Wasting-WS
    Neuronal Degeneration, Brain Atrophy -WS
    Basal Ganglion Calcification -WS
    Cataracts-WS
    Diabetes-BS, WS
    Alzheimer’s Disease-WS

    Symptoms of Werner’s Syndorme coopted from nuclear DNA driven apoptosis
    Poor Healing -WS
    Skin Ulcers -WS
    Thymic Atrophy-BS, WS
    Scaly Skin-WS
    Somatic Cancers- BS, WS
    Lipofuscin Accumulation-WS
    Arthritis-WS
    Peripheral Osteoporosis-WS
    Symptoms unique to #6
    Menopause-WS
    Breast, Uterine, and Ovarian atrophy and cancer-WS
    Prostate atrophy-WS, hyperplasia-WS, and cancer-WS
    Depression-WS?

    so I know this all looks quite complicated but if you could see the table as it exists in my published paper you will notice that Werner’s syndrome is connected with and drives all the other aging clocks, and each subclock is associated with just a unique set up aging symptoms

    the sub clocks are elucidated by studying the rapid aging diseases of progeria (male-aging) does not include cancer or dementia), and mitochondrial driven apoptosis and nuclear DNA dricven apoptosis (female aging) includes cancer and dementia…

    The name of the paper with the table is The Evolution of Aging
    by Jeff T Bowles Med Hyp 1998 it might deserve another look

    Reply
  5. Interesting that inflammation seems so central to every aspect of aging…

    In a desirable, acute response inflammation encourages clearance of no longer viable (senescent) cells, and the proliferation of replacement cells from the stem cell pool. Therefore the body can respond to stress and damage of various kinds.

    But excessive, chronic inflammation creates senescent cells at a rate greater than can be cleared, and either exhausts or locks stem cells in an undifferentiated state. Therefore the body loses its resilience.

    The question is what is the first step that causes this loss of homeostasis between an inflammatory response and it’s resolution?

    Blagosklonny points out the MTOR signal as being set unnecessarily high (see his Speeding Car paper that Alan Green mentions), which drives proliferation and shortening of telomeres, as well as geroconversion of quiescent/arrested cells to senescence.

    Interesting that you mention that ‘IKK-ß is produced by microglial cells in the hypothalamus of old mice ‘, from the Cai Group. Microglial cells proliferate and lose telomere length, and this could provide a link between MTOR, telomere loss and inflammation in the hypothalamus.

    Reply
  6. Hi all. I pretty much said everything in my 2015 paper (Towards an evidence-based theory of aging) even talking about Cai’s earlier work. It was clear to me then that the number of elements – both those that cause aging and those that prevent it – would be too large which is why I suggested ‘young blood’ (more literally plasma from young donors – and plasma exchange, to get rid of the ‘old plasma’ which is why I recommended HPE (Heterochronic Plasma Exchange) as the appropriate vehicle for doing this – yet somehow no one wants to do it right, or even do the basic proof-of-principle investigations which would be comparatively cheap. The fact that the blood is full of DNA, RNA both enclosed in membranes (exosomes) or complexed with proteins and that exosomes are filled with miRNAs that change the behavior of the cells that take them up (also discussed in that paper) and that miRNAs control age-related transcription,- was always something I took into consideration when coming up with the proper protocols for doing HPE.

    Reply
    • Harold,
      I always look forward to seeing you post here and also miss Gustavo Barja’s posts.
      I can only echo all of the previous praise to Josh for such intelligent and thoughtful blogs over and over- AND keeping always such an open mind.
      I am humbly grateful as a non-biology-educated structural engineer for all of the contribution I continue to see here.
      Thank you

      Reply
      • Say Clinton, as an aging person (as are we all) I’m not exactly an uninterested observer. I want this to work as much or more than anyone: I have no fear of death (‘the great adventure’) but I think we’ve only just tasted the potentials of life – and long lives will make that possible.

        Reply
  7. The good thing is people don’t have to hope for something in the future as people who follow Blagosklonny know there is very effective anti-aging formula with rapamycin as cornerstone of treatment here today. As the saying goes, “you pays your money and takes your choice.” The problem is since aging is not classified as a disease, traditional medicine has opted out and provides no guidance. You can’t go to a medical textbook and find a chapter on aging with an excellent discussion. Therefore everybody is on their own to try and figure out what is real and what is snake oil and when you reach the age of seventy something and begin to get a taste of what aging feels like, you know the stakes are very high.

    Reply
  8. August 9, 2017
    Josh Said: A small number of stem cells in the hypothalamus were found to keep the mouse young, in part by secreting these micro-RNAs.
    Av i Discussion: Number of researchers have shown that these hypothalamus stem cells decline with age. Also this new study from Cai show that adding Stem Cells from young mouse helps rejuvenate old mouse. Question: Is it possible to “add” hypothalamus stem cells by IPSC at hypothalamus via therapeutic non-invasive intervention ?

    Reply
  9. Question: Can Hypothelamus Stem Cell loss be slowed via a therapeutic intervention by lengthen telomeres of these Stem Cells ? Or does length of the hypothalamus stem cells have nothing to do with stem cell loss ?

    Reply
    • My general impression is that stem cell decline is usually a result of epigenetic disregulation. As Josh wrote it could be extremely hard to fix in situ. Genetically engineered stem cells might be a solution, once we understand what makes the epigenetic clock tick and how to slow it down.
      My understanding is that stem cells have tools at their disposal to maintain telomere length.

      Reply
      • Telomere loss leads to altered gene expression (epigenetic dysregulation so to speak), because of the way telomeres are looped around the histones they are come into close proximity with genes far from the end of the DNA strand. As they shorten, this changes. Stem Cells should be able to extend their telomeres as they replicate, but they don’t always do this. This is probably because rising body wide inflammation triggers NF-kB, which causes the Telomerase protein to locate to mitochondria and protect them from stress. If you want any references let me know, and I’ll try and dig them out.

        So telomere extension would be useful to give the Stem Cells a helping hand. It might also have to go hand in hand with a reduction of inflammation levels though.

        Reply
        • You make an interesting point linking telomeres and inflammation. My father was a true health fanatic for all of his life and had many biological markers of great health, not to mention that he had literally never been sick a day in his life up to the age of 92. At that point we sent off a sample of buccal tissue to a genetic lab at Harvard and he was found to have the telomere length of an average 20 year old. However, he then did develop psoriasis, a chronic inflammatory condition which wasn’t treated due to his advanced age. He died at 95 of abdominal cancer. I now believe that if his inflammation had been controlled he would have lived longer.
          Of course, now I would have started him on rapamycin at maybe 70 years .

          Reply
          • You have to be careful with measuring telomere lengths because you are really only getting a snapshot of their length in one part of the body at one instant in time. Your father wouldn’t have had the telomeres of a 20 year old all over his body, but the inside of the mouth renews very quickly, so at least it shows that here his stem cells were working very well. Interestingly mouth ulcers are the main side effect of rapamycin treatment, as slowed proliferation here is not ideal – but a small price to pay for slowed proliferation and senescence across the body as a whole. Who knows how long someone on intermittent rapamycin could live? Especially if they are as long lived as your father was without treatment.

        • what I know is that hTERT immortalized cells do exhibit epigenetic aging.
          http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=7383&pubmed-linkout=1
          they are not stem cell though.
          besides mice have long telomeres through their whole life and they too exhibit epigenetic aging. I believe TERT expression and telomere length are downstream of the epigenetic clock, though there can be some crosstalk as this is biology, not engineering.

          Reply
          • The danish study states, ” despite a clear inverse correlation between telomere length and chronological age, the precision of age predictions based on telomere length was relatively low.” clear correlation but not precise.

        • Mark said on August 10, 2017
          Stem Cells should be able to extend their telomeres as they replicate, but they don’t always do this. This is probably because rising body wide inflammation triggers NF-kB, which causes the Telomerase protein to locate to mitochondria and protect them from stress.

          Avi Conversation: I think we need to stay focused on the Stem Cells at Hypothelamus, and associated Stem Cells due to the new discovery of the role of these Stem Cells on “Aging”. I am an engineer, so my goal is to solve a problem via engineering. I want to design a vector vis synthetic biology and deliver “epigenetic” influencing therapeutics to say a specific breed of Stem cell at Hypothelamus to intervene shortening of telomeres. So should this therapeutic synbio vector we send to Hypotelamus target reducing inflammation or something or execute another task, or do both ?

          Reply
          • I am also an engineer, and I tend to view aging through that lens – like a machine going out of calibration. I think we do need to think about addressing stem cells in vivo, as ex vivo efforts seems ineffective so far. I think near term, telomerase treatment and a blockade on excess inflammation is our best bet on doing that. Resetting the epigenome completely would likely result in more stem cells being formed out of somatic tissue, which is possibly good, but also risky I think.

  10. I do fully agree with Alan and Mark that to a very large degree aging is at best a quasi-program driven predominantly by the mTor pathway. All cells are TOR driven, including those in the hypothalamus, and Rapamycin still remains our safest and best anti-aging weapon.
    There is another very potent anti-inflammatory agent at our disposal which is particularly active in the brain, and that is low dose naltrexone , which is very neuroprotective, and patients with all sorts of neuroinflammatory diseases are responding remarkably well to it. It’s certainly much safer than the NSAID’s with their GI bleeding and cardiovascular disease risk. It may be a very effective add on agent to rapamycin.
    Just as an addendum, it’s really not fair to classify Alan as “mainstream” since he was one of the very first persons anywhere to experiment on himself with weekly rapamycin therapy.

    Reply
  11. Response to Mark 2:41pm comment:
    Very insightful comment about mouth ulcers (aphthous stomatitis). This is viewed as disease of unknown etiology; but I agree with Mark’s suggestion that due to slowed proliferation. I have not had any mouth ulcers going on 18 months of weekly rapamycin. I view mouth ulcers as the canary in the coal mine, an early indication that dose is too high. Of course, transplant patients must continue high dose or face rejection and death. However, anti-aging persons could simply stop rapamycin, wait a few days for ulcer to heal and then later resume treatment if they like, at a lower dose or longer interval.

    Reply
      • Hi Paul,
        Very nice to read your comments.
        I view mouth ulcers as interfering in proper stem cell function to make mucosa.
        So for me, mouth ulcers indicate a toxic dose.

        Reply
  12. For an excellent discussion of telomeres see: “Telomeres in aging and disease: Lessons from Zebrafish”, Carneiro, 2016 (open access). Mice have very long telomeres, but zebrafish have short telomeres similar to humans so a very good model for study.
    In medicine, there is only recognized a few rare genetic diseases associated with lack of telomerase; but those conditions do resemble premature aging.
    In general, what looks like aging is the sum effect of the various diseases which comprise aging. It is possible that diseases of telomeres, will emerge along side diseases due to elevated mTOR, and diseases of mitochondria as a major aging disease.

    Reply
    • Nice article Alan – definitely to the point. To me the entire article devolves into one of the final phrases of the piece, ” it is important to further examine why metabolism has such a dominant effect on the stem cell ageing process and, once the link that promotes or delays ageing has been identified, to develop treatments that can regulate this link.”.
      For me, the entire purpose of the circadian rhythm, even before such mechanisms as the TTFL (transcription-translation feedback loop) clocks such as the Clock-Bmal1 circuit in mammals is to control metabolism, which is both the reason and the mechanism for these rhythms. What I mean is the rhythm was there – there at the beginning, before the genome ensconced it in a gene regulatory network. The network is not cell autonomous, which is why there is this discussion about the hypothalamus and the SCN – but the Cai lab already showed that the hypothalamus responded to damage elsewhere in the body – damage at a cellular level like the mitochondrial unfolded protein response. People are not taking seriously the finding of miRNA exosomal vesicles which appear to be intrinsic to the process!!!
      The ability to regulate this link between metabolism and circadian rhythms, that is to reverse the aging process, through metabolic means has been demonstrated many times over. There’s so much to do and no one’s doing it.

      Reply
          • Thanks Josh,
            2013 Cai paper was extremely interesting paper. Could you post the Solanas paper discussed by Harold K.
            The complete paper itself is essential to any understanding compared to abstract and especially newspaper article both being of very little value aside from notice that there was a paper on certain topic.

          • The Cai paper can be seen as illustrating one of great problems in deductive reasons; specifically, begging the question.
            The paper starts with a general assumption, aging is programmed. It then shows that hypothalamus controls aging. Conclusion, hypothalamus is in control of programmed aging.

            Paper could start with different assumption, aging is a disease caused by elevated mTOR. Finding: elevation of NK-kB effects hypothalamus stem cells and this promotes aging. Also major effect of elevated mTOR is increased activity of NK-kB. Conclusion: aging diseases caused by elevated mTOR and partly mediated by impaired function of hypothalamus stem cells.
            In discussion by Harold on how aging controlled by stem cells he noted how process can be partially stopped by caloric restriction. Caloric restriction causes low mTOR so again possible conclusion is aging promoted by elevated mTOR through effect on stems cells.
            My point is if start off with general assumption aging is mTOR related disease, you get one conclusion and if start off with assumption that aging is programmed, you get different conclusion.
            In both cases, the conclusion is dictated by initial assumption.
            Note that in all above papers they very carefully omit any mention of mTOR as this would open doors to pathways they don’t want to go down.
            A prior argument here started with initial assumption, menopause is programmed, therefore aging is programmed. Of course, I don’t agree that menopause is programmed. I view menopause as age related disease.

            Big risk in deductive reasoning is false initial assumption.

          • August 11, 2017

            Alan Green, MD comment: Fallacy of Deductive Reasoning Plus
            Conclusion: aging diseases caused by elevated mTOR and partly mediated by impaired function of hypothalamus stem cells.

            Avi Conversation: It’s a valuable non-deductive reseaned hypothesis. But we are still at the realm of basic science and not moving forward to translational engineering. Engineers like to build things, solve problems.
            Say, alternate hypothsis is worth testing.As an engineer, I would like help in translational thinking to say, ok, let’s send a probe, a synbio designed probe that reduces mTOR, over a period of time. We might use a simple biophysics tool to open the blood brain barrier temporarily to allow our synbio probe in. Of course would start with mouse, then a higher mammal, before we can get permission to try on humans. So, the challenge here is to design a synbio probe that will allow us to reduce mTOR, over a period of time, with repeated probe delivery to hypothalamus, and then measure the impact. This is the engineering translational approach to solving a problem.
            Any suggestion how the synbio prob should have to test if this hypothesis can be tested by an engineering approach ?

  13. To add to the clocks listed in the original post — I stumbled upon a video of a TED talk by Andrei Gudkov, who says endogenous retroviruses in our DNA are the sources of species specific clocks, and the cause of aging. It sounds like a credible theory to me. But he doesn’t go into enough detail to satisfy my curiosity about it. Does anyone have any details and/or thoughts about this possible clock?

    Reply
  14. Alan you offer the picture of a snowball effect – once NF-kB is activated (as by IL-1b or TNF) you get an activation of mTOR (which complex or both?) which produces an activation of NF-kB and round and round, bigger and bigger until some sort inflammatory cascade kills us? That’s more a timer than a clock and isn’t what happens. Since it was clear from the very first C. elegans mutants daf-2 and age-1 (insulin receptor and PI3 kinase – components of the IIS) that life span is reduced in order to accomplish other, more necessary life goals (does Nature, or even little us, care about whether an individual nematode lives three weeks or six months – it’s fulfilled its life’s objective after about two weeks.) The fact is that lifespan is a species trait – that it’s apportioned in a non-obvious way (why rat and squirrel of the same class and order, and size have a ten-fold diff in lifespan, the fact that killifish adapts its lifespan to the length of time pools remain filled in equatorial Africa – and so many other show that the sequence of aging changes follows a stereotyped course (and hence apparently ‘programmed’) from worm to man – but ‘programming’ is very loosely used. The ‘rate-of-living’ hypothesis would make us believe that we’ve inherited a certain amount of irreplaceable energy (each cell of us, that is) that we play out over time – spending them on tidying up the results of OXYPHOS, like the “free radicals”.
    Again, in primitive animals like worms – life span can be extended ten-fold using mutations and treatments together – and those diseases of aging are put into the far future of the animal -so you can see the scaling effect – as though their “play” was already written in sketch form, wherein the actors could ad lib – and the rate at which they spoke their lines determined the length of the play. Now, not all age-related transcriptional profiles similarly scale, about a third of transcripts do in C. elegans.
    So far as menopause being a ‘disease of aging’ – has anyone (woman) ever been free of this disease? In the worm for example – the sequence of event in the hermaphroditic organism is first the sperm cells are produced, then the eggs are produced, matured, inseminated and after a few days its all over – no more eggs will be produced – and the animal will live thereafter for about the same time as it did up till then. There no talk about a disease of aging – the process is entirely ‘programmed’ (and now when I say ‘programmed’ I mean something like developmental programs more than computer programs,, one stage leading to the next.

    Reply
    • While I view your discussion as total nonsense; it is important from political perspective.
      If aging is recognized as a disease, it is part of world of medicine and aging can be treated like other diseases.
      If aging is considered as natural or progragrammed; then anti-aging medicine can be outlawed.
      So nonsense doesn’t change science; but it can allow laws that stop treatment of aging.

      Reply
      • Understanding aging starts with Presbyopia. It is hardening of the lens due to loss of crystalline. Everybody gets it from 45 to 65.
        Is it a natural part of aging or is is a disease of aging?

        Accepted dogma is Presbyopia is not a disease as everybody gets it. My point of view is Presbyopia is a disease.

        Reply
        • Almost everybody gets presbyopia, not everyone. I am 61, and do not have presbyopia. I have early cataracts, but have not had cataract surgery. I wear eye glasses for myopia and astigmatism, and have been taking them off for reading for years.

          Reply
        • Alan it was recently discovered that germline stem cells once done with their role in puberty immediately send a signal to the ubiquitous proteasome system to bring down its efficiency by 70% or more. So aging starts just after puberty – not the summation of mutations or wear and tear, etc. Proteins have a few of the critical roles in our biology and as soon as the reproductive organs are formed the chances of misfolded proteins and eventually aggregates which are so harmful is significantly increased. How can one explain this except with the programmed theory?

          Reply
          • The mTOR protein kinase in ovarian cells is in overdrive to ensure that menarche is achieved by the age of 12 or so in order for reproduction to begin since lifespan was only 25 years. But, like a train going 100 miles an hour without a break system, TOR never slows down and the result is ovarian failure between 45-55 years of age.TOR is also responsible for aging diseases of all organ systems, not just the ovaries, albeit somewhat slower. Rapamycin is for now the most efficient way of slowing it down.
            By the way you have a superb website and your blog on natural substances for cancer prevention was truly outstanding Akshay!

          • Thank you very much Paul for your kind comments on my website and blog. Coming from someone who is recognized in the top 5% practising doctors in USA is heartwarming. Treating 80,000 patients for weight loss with 95% success rate is a remarkable achievement! As you know aging hits us with a double whammy in the middle age – intestinal cholesterol absorption doubles in efficiency and hepatic LDL clearance halves! When all other efficiencies are falling cholesterol absorption efficiency doubles. This program or quasi program is devious! We should probably work together on metabolic syndrome caused by aging.

          • Hi Akshay,

            For complete discussion of your question need to start with Blagosklonny paper, 2006, “Aging and immortality:quasi-programmed senescence and its pharmacologic inhibition.” Then jump to 2017 paper “From rapalogs to anti-aging formula” and review references.
            However, want to comment about misfolded proteins and their aggregation. Misfolded proteins are major factor in type 2 diabetes and in Alzheimer’s disease, two very prominent diseases of aging. The role of beta-amyloid and Tau as misfolded proteins in AD is very well understood; but role in diabetes is fairly new. Insulin and amylin are both produced by beta cells of islets in 20:1 ratio. Increased insulin due to insulin resistance means increased amylin. However, amylin in high amounts becomes a misfolded protein, aggregates, destroys beta cells which results in type 2 diabetes. The point is these are diseases. Diseases happen. You don’t need to program diseases to happen; diseases find a way to happen all by themselves.
            This argument goes back to classical antiquity. . Around 5th century BC, Hippocratic theory classified aging as disease. Then Galen 200 AD declared aging as natural. His reasoning was: (1)disease is abnormal function, (2) aging is universal, (3) that which is universal cannot be abnormal, (4)Therefore, aging is not a disease, it is a natural process. Programmed is modern concept for natural.
            Traditional medicine of today had adopted the 2000 year old logic of Galen.
            Only in math can things be “proven”. In Biology it is all theory. The problem is classification of aging as natural put it outside medicine. Not classifying aging as a disease can have dangerous consequences and very unfortunate for advancement of treatment of aging.
            My objection to all above papers is they start with general proposition that aging is natural and programmed. Then they find that stem cells in hypothalamus involved in health and aging. If they began with concept that aging is a disease; they would conclude that changes in hypothalamus stem cells is part of the disease of aging.

      • Alan, you are out of line and rude, in your remark here.

        If you wish to be read, respected, and replied to, it’s important that we all abide by simple courtesy.

        Calling Harold’s remark ‘total nonsense’ is destructive and lacks courtesy.

        Reply
        • Thank you Bill, I’ve devoted a lot of time to trying to understand aging and I hate for my hard work in trying to understand it be dismissed out of hand.

          Reply
  15. Nice, you characterize my views as nonsense – ditto yours. Rapamycin delays aging, it doesn’t stop it. That’s no way to conduct science – do you have a reason, a specific objection – or just opinion putting someone down with an ad homenen argument? I guess our president now sets the tone for scientific debate and alt-science?

    Reply
  16. So ‘changes in the hypothalamus that result in aging is a symptom of the disease aging? – I don’t think so. What does ‘disease’ mean? If it’s universally present in nearly all living things is it a disease? If you can find some mammalian exceptions to aging, I’d consider it a disease. The way to tackle aging is by tackling the diseases of aging. What makes them diseases is that not everyone gets them. Everyone ‘gets’ aging it’s part of the normal course of metazoan life! Of course the best way to put off the disease of aging is by putting off aging.

    Reply
    • As I pointed out in prior comment that is exact same argument of Galen in 200 AD. After 1800 years the same argument starts to smell bad. However, that is same argument FDA has for not recognizing anti-aging drugs as legitimate drugs for testing and same reason aging is not discussed in medical textbooks; so argument is not nonsense to everyone; but nonsense to me.

      Reply
      • ‘Nonsense’ means it doesn’t make sense. Aging is nearly a universal occurrence among metazoans and a significant number of protozoans, the ciliates seem to have invented (or rediscovered) both sex and death – and pretty much since then, with some rare exceptions, animals (and plants) have been aging and dying – and the same genetic systems, including mTOR, including AMPK, including the MAPK signaling system, including the wnt signaling system, including a number of transcription factors like Nrf2, FOXO, GATA’s, sirtuins, control aging from worm to man. mTOR is amenable to inhibition, and undoubtedly has many inputs and outputs – but that doesn’t mean because you have that hammer – aging is that nail.
        There does seem to be a fundamental problem with stopping growth and aging.
        “Disease” is a matter of definition, a normal occurrence of a condtion – like ‘growth’ is not a disease even if it’s unpleasant. The fact that aging need not occur in organisms like planaria or hydra – doesn’t occur on the cellular or orgasmic level – means it need not occur, the fact that this non-aging is so limited is an indication of how useless it is to the living world. Yesterday I would have thought that mankind was beyond ‘natural selection’ and worthy of eternal youth – but today, I don’t think so. Sad, just when it’s possible.

        Reply
  17. Definition of disease: Wikipedia:
    “A disease is a particular abnormal condition that affects part or all of an organism that consists of a disorder of a structure or function. The study of disease is called pathology, which includes the study of cause.”
    There is nothing in definition of disease, which includes the criteria that a disease effects affects some but not all. All living things have very much in common. An extremely virulent disease could potentially kill everybody; but it would still be a disease.
    I am a board certified pathologist; so it is my area of medicine that actually studies disease.
    Aging fits the definition of disease perfectly.
    A recent paper, Should we treat aging as a disease? The consequences and dangers of miscategorisation.” Faragher, 2015, Frontiers in Genetics, is an excellent discussion.
    The stakes are extremely high. The abstract begins:
    “The aging of the population represents one of the largest healthcare challenges facing the world today. The available scientific evidence shows that interventions are available now that can target fundamental “aging” processes or pathways.”

    In my opinion, the failure to classify aging as a disease represents the greatest barrier to providing protection to millions from the ravages of aging.

    I have recently begun a clinical medical practice to provide aging protection based upon the best science of the day. In the past 10 years there have been extraordinary scientific advances in understanding aging and providing protection against aging. The legitimacy of any such medical practice is very much threatened by the concept that aging is not a disease.

    Reply
  18. Of course you either missed the word “abnormal’ or you need a definition of it – something like ‘unusual’, or, ‘departing from the norm’? As aging is entirely normal and lack of aging is surely a departure from the norm, aging cannot by that definition be considered a disease.

    Reply
    • Yes, except like blaming the Charlottesville tragedy on both sides, there’s a logical mistake being made. Let the ‘people’ decide who’s right and who’s wrong – I never said (or indeed thought you were an idiot) but that you were wrong and a very rude person, but not an idiot.

      Reply
  19. If aging is indeed controlled by the brain as this post informs inflammation seems to be main villain common in all neurodegeneration. There is a new study that suggests that FDA approved drug galantamine mitigates inflammation in the brain and protects neurons from degradation. Entire brain including the hypothalamus benefits from reduction of low grade chronic inflammation. If hypothalamus does control aging then we should see benefits over a period of time. The brave may dive in. I have started a self inflicted trial on myself with 4mg dose first every alternate night. Let me share with you my experience from the first pill. I had deep improved sleep. The brain did feel different – more fresh and sharp. Felt a sort of high till late afternoon after which the effect began to wane. I did feel a little bit of nausea around that time as the side effects mentioned (that is why I recommend starting with low dose) but it kind of settled. I missed that feeling from the first half. Will post if any subsequent dosing brings out anything further. Please do read the side effects and the drug interactions carefully. It should be a prescription drug in your country so you will get the benefit of your doctors opinion.

    Reply
    • Akshay, Kudos for your self experimentation! I assume you are looking for prevention and not cure so I’m not certain of the long term effect of a chronic increase of acetylcholine in a normal person. Perhaps you are aware that Saffron is safe and effective in mild to mod Alzheimer’s with a significant increase in cognitive function ( Akhondzadeh et. al. 2010 J Clin Pharm Ther)
      Another study of 54 patients showed saffron as effective as the anticholinesterase donepezil ( Akhondzadeh 2010 Psychopharmacology). Another showed curcuminoids both prevent and treat Alzheimer’s through anti-inflammatory and strong lipophilic action to improve cognition, reduce amyloid plaques, delay degradation of neurons, and improve overall memory ( Ahmed 2014 Phytother Res) and also attenuates hyperphosphorylation of tau proteins while enhancing its clearance and modifying microglial activity ( Tang J Alzheimers Dis 2017)
      These may be as effective for your purposes and safer perhaps!
      Website selfhacked has even more.

      Reply
      • Paul, yes was looking at prevention. Yes any new intervention that is the risk – long term use unknown although it is a FDA approved prescription med. But I absolutely agree with you to consider natural alternatives. From my website you know my predilection for natural alternatives when available. I wasn’t aware about the anticholinesterase action of saffron and curcuminoids. Thank you for bringing that to my attention. Will switch immediately. No wonder your practice is so successful!

        Reply
        • Thanks. And see this Akshay ” Photobiomodulatiom with near infrared light helmet in a pilot trial in dementia patients testing memory and cognition” where infrared light in the proper spectrum is incredibly brain anti-inflammatory and clinically effective , while being very safe. For an in depth discussion see ” Turning on lights to stop neurodegeneration” 2016 Jan 11 online . Since you’re an engineer maybe you could design a helmet!

          Reply
          • Thanks Paul. Sounds very interesting. I will check it out immediately. I want to share some good news with you. I have come up with my own deduction of the mechanism of aging and also have put together a multipronged all natural protocol to upregulate some of the key repair system efficiencies that drop as we age. I have built a team one of whom is a Cardiologist and surgeon ranked no.3 in one list and two are PhDs who have done clinical drug discovery research at major global pharma firms – GSK and Pfizer. After they understood the science they too got excited. I now have all the commitments I need to fund pre-clinical murine trials to be conducted in collaboration with a reputed University Lab. I am nervous and hoping that we get good data results so that we can go to human clinical trials in collaboration with a reputed hospital. One of the investors is the Cardiologist. I will post our results here. Please wish me luck.

          • Thanks Chris. That’s exactly it. That may really be the wave of the future in both treatment and prevention of dementia without drugs. I think we’re just beginning to understand the importance of infra-red on mitochondria and neuronal health and preservation.

  20. Do anyone in here really believe that it will never be the case that humans will stop the aging process as we know it?

    Reply
    • Hi Aaron,
      We can stop, the aging process as we know it, today. The real question is when will people believe it. People will believe when they see TV commercials touting an anti-aging drug. That means a very expensive brand name drug approved by the FDA which is probably more than 20 years away.

      Reply
    • Personally, I won’t believe it until I see the likes of George Church, Michael D. West, Michael B. Fossel, Aubrey de Grey, et al. literally looking 20 or 30 years younger themselves in new videos on YouTube.

      Reply
      • Hi John,
        2 years ago I couldn’t walk my dogs as got chest discomfort, shortness of breath and tired walking up a small hill. Now this summer I cycle 1000 miles a month and feel great. That is what anti-aging looks like, the reversal of age-related cardiomyopathy. Kaeberlein’s dogs had same results as me. Old dogs in few months were running around like young dogs with excellent cardiac function that was confirmed with echocardiogram. Anti-aging is also loss of age-related midline obesity so instead of having an old man pot belly, you have a 32 inch waist line. You are correct that don’t need obscure lab test to see anti-aging; you can see the change from a block away. Nobody knows how great it is to feel young until you feel old and then turn back the clock. “Individual results may vary.”

        Reply
          • Hi John,
            I am Alan S. Green, M.D. in Little Neck, NY (NYC)
            You can see a discussion on my website: rapamycintherapy.com.
            It is a detailed discussion about 25 pages.
            I have no original ideas aside from my own personal experience. It is the world according to Mikhail Blagosklonny. My practice is the application of the ideas of Blagosklonny to clinical medicine. So if you think Blagosklonny is the one of the greatest scientists since Charles Darwin and Louise Pasteur, you might be interested.

  21. Check out new study published today on cardiac progenitor stem cells with systemic rejuvenating effects. Further notes that maybe driven by secreted exosomes! Wow this is coming together quick. Ditch the rapamycin.

    Reply
    • The article is from CNN health entitled “Unexpected fountain of youth” found in cardiac stem cells. News article is from recent paper in European Heart Journal. Old rats with heart failure were in injected with cardiac stem cells from newborn rats. The stem cells from newborn rats improved heart function in rat model in which had created heart failure. The interesting “Fountain of Youth” issue was old rats showed other rejuvenation like effects like hair growing back faster and few other effects. This was considered as due to exosomes containing DNA in young stem cells.
      Capicor, the company that makes the stem cells says plans are for use in heart failure and muscular dystrophy.
      Medically the stem cell therapy would appear to have excellent potential for heart failure patients.
      Big problem, aside from few exceptions, most stem cell use illegal in USA. Note this was European study. So if you have heart failure in another 10 years, maybe could go to Europe to stem cell treatment center.
      This is opposite of use of rapamycin which is to prevent disease, prevent heart failure. This study is treatment of heart failure with stem cell therapy.
      This is totally consistent with American approach which is not about prevention; but rather to have extremely expensive and very complex treatments for end stage disease. Idea of rapamycin therapy is prevention, stay healthy, avoid age-related disease like end stage heart failure.
      This is not to say stem cell therapy doesn’t have great potential. Biggest obstacle
      in USA is illegal and all treatment would need to be approved by FDA.

      Reply
      • Very interesting but it is not clear to me what is the novelty of the approach. From the article:
        “The novelty of this bit of work is, they started to look at more precise molecular mechanisms to explain the phenomenon they’ve seen in the past,”

        Also, Capricor stock has been divided by 200x over the last 10 years and have recently experienced a trial failure in Heart Disease so it would really be good for them to have a big success.

        Reply
      • 1. I doubt European regulatory bodies are more relaxed than FDA. My feeling is they are following FDA recommendations and practices.
        2. You may not need any kind of stem cell therapy. You may be able to harvest those exosomes from iPSC farms without any potential problems of cancer, immune reactions etc.

        I believe this type of cell-cell communication (exosomal) have been very much overlooked, I just started googling for it and already found interesting papers that link epigenetics and exosomes as well as development and exosomes, cancer and exosomes.
        One thing I am very curious about is how these exosomes evade the immune system, and or how is that no pathogene exploits them. I assume if this loophole was exploited by pathogens we would have known about them earlier.

        But maybe, thats how viruses started… a long time ago and they just became more streamlined versions of exosomes.

        Reply
      • “Having someone else’s stem cell injected into me would give me the willies.” Starting with a needle biopsy, any of your cells can be converted into pluripotent stem cells and then further into other stem or progenitor cells – time consuming and labor intensive (until robots can do it), but it’s been demonstrated. So you can use you own stem cells.

        Reply
  22. aging is due to shrinking of the dna strands which occur in various cells which divide, In 3D the way the dna arrange itself to place in the nucleus the genes which are used outside of the bundle and the non expressing genes Inside (genes outside ie expressing themselves are determined by cell differentiation) is modified along time, ,all this is of course due to the depletion of telomerase after we were born,
    species which express telomerase correctly at the right dose in all dividing cells of their body dont age because the epigenetic do not change at all over time, Old cells where télomères are restored just to restore the dna lenght of Young ones -no more no less- (and consequently shape) works epigenetically as Young cells,

    Reply
  23. The standard evolutionary explanations of why we age have never seemed plausible to me-but it seemed counter-intuitive to me that we would actually be programmed to age.

    I finally hit me that evolution would program us to age for the same reason it developed sexual reproduction.

    Animals need sexual reproduction in order to give them genetic variation. Without this genetic variation, parasites, diseases, and other enemies would eventually come up with ways to crack our defenses. Some people call this the “Red Queen” theory.

    if you think about it a bit, it seems obvious that organisms that didn’t age, would also end up with a lack of genetic diversity. Give me back my 20 year old body and health and let me keep the wealth, experience, and general craftiness I now have. I would then get nearly all the girls I didn’t get then, and only a few real 20 year olds would be able to compete with me. But, in any population where the older males got most of the females, and kept on getting them indefinitely, genetic variation would be severely reduced, and the species would be vulnerable to its enemies. Of course females also compete, and in an ageless species, older females would dominate younger females and monopolize resources.

    Pardon me if the above seems just too obvious, and I’m sure that many others have already written about this.

    Reply
    • Robert Kane Pappas
      Richard Morimoto at Northwestern University produced a paper in July 2015 that says that upon early adulthood, i.e. soon after reproductive maturity, a switch is thrown and there is a quick decline in biological quality control. The HSR (heat shock response) are repressed. This to me is how and when the aging program is initiated. His study was done on worms, but may extend to us.

      Reply
  24. Dear Gabor, those were good citations. One in particular, the one by Tom Rando – and the reference given to the work in C. elegans concerning a trimethylation complex that affects lifespan – I think solve your problem.
    It was exactly the 2012 paper by Tom Rando, in which he asks about the possibilities of changing the epigenome through Yamanaka factors to bring about reversal of aging and whether aging can’t be reversed without changing the differentiated state of the cell. I wrote him and told him that the 2005 experiments he performed in conjunction with the Conboys, showed that you could change the age-phenotype without changing the differentiated state of the cell – and it was following that that Wyss-Coray – under Tom, began investigating human blood transfusions a al Alkahest.
    The second paper about the histone trimethylase complex and lifespan shows a similar thing – the epigenetic state of cells is not determined by any sort of internal ‘template’ or ‘mask’ but by signals from other parts of the body (as the hypothalamus paper at the center of this forum indicated) – in the case of the trimethylation complex in somatic tissues regulated by the ovary. Of the case of daf-2 mutants causing life extension when only expressed in two (VMI) neurons in its ‘brain’.
    So the epigenetic state of a cell is controlled by transcription factors which are often histone modifying enzymes in their mechanisms of action, other histone and non-histone binding proteins (like the HMG proteins) and all sorts of functional enzymes and ribozymes concerned with transcription and splicing, functional long, non-coding RNA molecules – etc. all of which function in determining chromatin state, whether open, closed or ‘poised’. So my point here is that ‘it’s complicated’ but that among the factors – important factors controlling chromatin state are the cell’s metabalism – the methyl groups come from SAM (S-adensyl-methionine), the acetyl groups from acetyl-CoA (and lots of other acyl groups are also added to histone tails) and removing acetyl groups takes oxidized NAD (NAD+) all of which are available at some times and not others (as levels depend on a circadian clock) and external signals maybe completely change chromatin markings and cell behavior – the clearest example is the receipt of hormones causing drastic changes in transcriptional activities.
    So to boil it down – the histone code is the working language of the cell, where it tells itself or is told how to behave depending on circumstances. Those epigenetic changes seem to be late and superficial compared with the changes corresponding to differentiated phenotype – remember young blood plasma alone has been shown to change the age-phenotypes of a large variety of stem and progenitor cell types – those changes no doubt occur at the epigenetic level but are externally controlled.

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    • Thanks! Now that we have proof that nucleotide carrying exosomes affect organismal aging I think the pieces are falling into place.
      Epigenetic clock can be reset with Yamanaka factors, so there is a way to do it without dedifferentiation.
      Exosomal communication between cells maybe a good way of synchronizing the epigenetic state. Cells can directly exchange different RNA content that can act on other chrchromatin.
      Exosomal therapy is probably much much easier to do than stem cell therapy also much less risky.
      I wonder if feeder cells or serum utility is not at least partly due to exosomes.

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      • Dear Gabor,
        When I’ve proposed protocols for HPE (heterochronic plasma exchange) I’ve always taken that exosomes and protein complexed polynucleotides would have a direct effect on aging. There are precautions that must be taken to make sure the exosomal delivery is intact. I don’t know why I thought so, but I think you will find reference to them in my 2015 paper (Towards and evidence-based model of aging) – I always believe this very direct transmission of information would be important in aging and always believed that HPE using the proper techniques and schedules would replace the exosomal content of the plasma and that the plasma communicated with the stem cell niches.
        Sincerely,
        Harold

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        • Thanks again. I wonder if anyone is doing very simple experiments, like growing different kinds of embryonic tissue in dish like MEFs or iPSCs and then injecting the liquid from the culture into aging mice.

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          • People have done such basic experiment with mixed cultures of hold and young stem cells – and found that the young stem cells could rejuvenate the older ones. Now with a greater knowledge (exosomes) as to how that age-information is transmitted, we should be doing those sorts of experiments – to begin with. Following that, the characteristics that cause exosomes to be taken up by some cells (and not others?), and the contents of these exosomes – how do they produce their youth-inducing effects – which miRNAs/mRNAs/lncRNAs/proteins/enzymes do what? It really depends on to what extent these exosomes influence aging – I wouldn’t imagine they’ve be all of it – but I don’t know. As I said, I supposed in my protocols for HPE that exosomes would be important constituents.
            Yes, it seems that this is an empty field – the most dramatic and hopeful experiments concerning the only known process able to produce in situ rejuvenation in living animals, and at the cellular level, isn’t being investigated by those whose entire careers are based on self-deception and clinging to an untenable hypothesis – denying the evidence by never mentioning it and ensuring that no one undertaking that challenge will be supported or published.

          • Dear Harold,

            I have just finished your 2015 paper. It is very concise and has moved me away from the intrinsic view towards the extrinsic view. I understand you feel frustrated as your research ideas did not gain enough attention? But isnt HPE something similar to what Rando and Conboys are doing? Do you feel it is very hard to obtain a grant for HPE? Could you possibly be much luckier with crowdsourcing? If the general public understood the opportunities there would be some financing I guess. However I guess one would need funding on the order of 10s of millions of dollars just to do the experiments with the mice.
            I also read the MDSPC paper.
            https://www.nature.com/articles/ncomms1611
            Interestingly it seems they did not have results with MEF cells, though I guess they only tried it with implantation, and probably the MEF cells didnt engraft. I wonder MEF co-culturing could have helped?
            Also there was a reference to a 2007 Rando paper stating that aging in hematopoietic cells might be intrinsic afterall.
            Regards,
            Gabor

          • Note for GaborB,
            Harold’s plan involves transfusion, a kind of plasmaphoresis. This is highly regulated by FDA. It would require approval by FDA to do tests an approval of the product.
            A basic tent of medicine is medicine treats disease. The FDA supports this policy and only licenses products which treat disease. The ongoing metformin study which somebody mentioned here was an attempt to coax the FDA into considering aging as a disease,

            The entire basis of Harold’s treatment is idea that aging is not a disease but something controlled and regulated by the body.
            Therefore, Harold’s treatment would never be approved by FDA either for testing or for human use.
            So you are talking about raising hundred of millions of dollars for a procedure which would never be approved by FDA.
            This discussion doesn’t even touch the merits of the idea which is far outside current ideas about aging which focus on mTOR, mitochondria, telemeres and how aging happens on a molecular and subcellular level.
            Treatment of aging could be divided into that which is here today and science fiction, something in the distant future in a different kind of world. What is here today is caloric restriction, physical activity, natural supplements and FDA approved prescription drugs.
            You have been having a very long discussion about science fiction.

          • What nonesense – can you imagine that if the procedure works the FDA would ban it (or if it did that would matter – there are many nations that would allow it)? It’s a variety of plasma exchange (with some precautions taken) – an already approved procedure for a variety of things – like adding or subtracting substances from the plasma – and it’s use would not be to treat aging – but to treat the diseases of aging – the restoration of youth would simply be an unfortunate side effect. Can you imagine that this works and is never tried because of negative people like Alan? That would indeed be a tragedy for the entire human race. The only thing that matter is whether it works – and evidence indicates it might. Rejuvenation is really the only way life extension will work – any other known means of life extension – like rapamycin or resveritrol (known to work in some animals)- extends the youthful period of life no more than it extends the senescent period. That’s been shown over and over.

  25. Exosomal therapy sounds exciting but I guess it is already part of young plasma? But the challenge remains as to where is the clock that is driving all of this – how does biological system as a whole decide when to grow teeth, when to launch puberty when to start aging. Besides the ‘when’ there is also instructions on ‘what’ to do at a particular juncture. The day we discover wherein lies this clock we may be able to address the cause of aging. And then to confuse us there are pertinent questions from other scientists as to whether there is a clock at all.

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    • Dear Akshay,
      Who has expressed doubt as to whether there are biological clocks – chronobiology is a well-established branch of biology, something like a third of all genes are clock-controlled, some directly by having an ‘E-box’ recognized by the transcription factors whose entry to the nucleus and binding to DNA are involved in circadian rhythms of abundance and reactivity, but my guess is that you are specifically talking about an aging clock? If so the best evidence (to me) comes from studies of mutants or animals raised under conditions which increase or decrease lifespan – under these condition you see that the basic structure of the life-span is kept – embryo, larvae (in the case of some, could be generalized to ‘children’), young adult middle aged adult old adult – with the same phenotypes in all cases – however in short-lived animals (short-lived for their species) each stage takes a shorter time, and in extended-life animals, each stage takes a longer time (including the stages of decrepitude). Fontana’s lab showed this with C. elegans – but it applies all the way up the hierarchy.

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      • Harold yes the aging clock or the central clock that triggers major changes in us in a linear fashion from fertilised egg till old age. If we can see aging as an orchestra and all the different pathways and sub pathways as musicians I am trying to understand where is the conductor. Although we can’t see the conductor we know there is one by observing the musicians. All our recent efforts in the anti aging community has been towards discovering the musicians and trying to influence them to change the tune (symptoms of aging). If one day we can decipher the conductor then hopefully we would need only one intervention to stop or even reverse aging. There is now sufficient evidence to show us that theoretically reversal is possible. If only…..

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        • You seem particularly clear-sighted, yes – instead of trying to correct each out-of-tune or out of sequence musician, correcting the conductor – in your analogy – would be the better way to get the desired harmonious result. Using HPE is in essence intercepting the blood borne commands of the old body and substituting the communications of the young body (a fresh young ‘conductor’) with its cells.

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  26. The point is everybody reading this website will be dead before Harold’s idea becomes actual FDA approved treatment used in USA by physicians.

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    • The point is that if rejuvenation worked, it would solve many of society’s problems – not the least of which is the coming of the baby boomers to senescence. That the FDA would approve it is shown by Alkahest which is doing something similar and by our own Jesse Karmazin whose Ambrosia is doing well – but so far as I’m concerned no one is doing it correctly. So FDA has already approved similar for experimental purposes and some companies are already trying to harness the technology – without even doing the required proof-of-concept studies or exploring important variables.

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    • Eventually- but there’s so much to know- it will be years – and that’s of course making the untoward assumption that that is all there is – which I don’t believe.

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  27. Seems to me that Simulation of what Dr Katcher calls HPE is possible. How close? Don’t know for certain, but I believe very close.

    1 – Slough off Aging Factor tainted plasma via Red Cross blood donations. The RC is in great need of platelet donations. A lot of plasma is also taken during platelet apheresis. (I got rid of 2.5 liters of plasma in 4 months.)

    Assumption : Most (all?) aging factors are inflammatory or triggered by inflammation.

    2a – Trigger Muscarinic – Acetylcholine Receptors in the Hypothalamus which triggers the Cholinergic Anti-Inflammatory Pathway to reduce inflammation in Splenic Macrophages. Doing so has been shown to reduce inflammation in the circulation (see Tracey youtube discussion in 20 minute talk to DARPA in 2016).

    2b – Trigger Heat Shock Protein 70 to reduce inflammation.

    This isn’t a silver bullet that cures aging, but it is a bullet that can be fired Now.

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  28. I think this study goes in the face of the extrinsic / systemic clock hypothesis.
    http://www.haematologica.org/content/102/8/e321
    There is an older article corrobating the findings

    Although there is a spurt of rejuvenation after the hematopoietic stem cell transplantation, epigenetic age of blood continues to be correlated to the donor instead of the recipient.
    Again I believe those parabiosis – exosome mediated effects might be just due to alleviating some problems at tissue level healing, but not really making the individual cells any younger.

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  29. Josh,
    How is this theory of aging different than Olivnikov’s Chronographic Theory of Aging as detailed in his 2015 paper: “Chronographic Theory of Development, Aging, and Origin of Cancer: Role of Chronomeres and Printomeres”?

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  30. Good article. I can confirm this theory with a clear conscience. I have long been working with biopeptides (= information molecules) isolated from the cells of various organs and tissues of healthy young animals (pig, calf). These biopeptides exactly stimulate protein biosynthesis in the human cells from which they originally came. We also develop and produce preparations for naturopathic practitioners with these substances. We have seen that with regular use of these peptides, the functions of the organs (from which these peptides are derived) can be improved or maintained. Particularly effective are pineal gland peptides. The pineal gland is also considered a biological clock. I agree with Josh that you can have a very good anti-aging effect by turning back several biological clocks. I can well imagine that combination of hypothalamic peptides + pineal gland peptides would lead to a very good effect. However, I must mention at this point that the use of these peptides only rejuvenate the body’s endocrine system. In order to rejuvenate the entire body as possible, functions of other systems must be rejuvenated, such as immune system, nervous system, etc.

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  31. How would RNA reabsorbed by the body via gametes (thinking Celibacy) affect the Hypothalamus and it’s Micro RNA function? If at all?

    Same with other nutrients that are common in Semen? Phosphatydlcholine for example.

    Study was done on Korean Eunuchs that lived in palaces during Monarchical times in that country. Royals lived on avg to 45-50. Eunuchs 65-70

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  32. Nice Josh, I too am of that ‘wild-eyed’ group and I think we’ve already proven your contention. I too follow Cai’s work and you adequately quoted his results, but he found that exosomes derived from the conditioned media of neural stem cells cultured in vitro had the same life-extending effects as actually injecting the stem cells themselves into the hypothalamus. One ‘minor’ point is that NF-kB (that’s ‘kappa’ B) and IKK-beta are not cytokines – NF-kB is a transcription factor which is induced by various things including cytokines, esp. IL-6. IKK-ß is a protein to which NF-kB is joined (like many transcription factors NF-kB and its inhibitor IKK-ß form a pair preventing NF-kB from entering the nucleus. Only when the bonds are broken (say by oxidation damage from excessive levels of ROS or by induction through cytokines) NF-kB can leave the nucleus and do its job – which includes the elaboration of the same cytokines (TNF, IL-6 etc.) as induced it – and also prevents apoptosis and leads to cellular senescence. In one study I read, old mouse skin treated so that NF-kB would leave and not re-enter the nucleus of the skin cells (in vivo, on a live mouse), showed a complete transformation of the structure of that aged skin to that of a newborn mouse. So, yes NF-kB is part of the problem. Also please note that while Cai did get life extension – it was not that much. Cai himself states that the hypothalamus is a master clock that controls tissue ‘slave’ clocks (in Hindi the word ‘golam’ means slave – a big insult is to say a man is his wife golam – note the resemblance to the Hebrew ‘golem’) – anyway as you say there are many clocks. The circadian rhythm that you mention is an alternation between a oxidizing cytosolic/nuclear environment (during energy generation) and a reducing one (for redox repair) – and though there is transcription translation feedback look that controls it – there is also an independent system (present in red blood cells – even though the have no transcription) that relies on the omnipresent redox enzymes – glutaredoxin, peroxyredoxin etc (the most common proteins in a cell). I believe that this cycle has much to do with cellular aging. The entire process is however systemically controlled – a big difference in Cai’s approach is that he assumes aging is systemic while everyone else, including Lopez-Otin, (Hallmarks of aging) assume aging occurs at the cellular level (which it does, but is controlled at higher levels).

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