Aging Biomarkers - Which Ones Are The Best?

RoeyRoey Posts: 157 XPRIZE
edited July 15 in Age Reversal
In this competition we want the competitors to demonstrate that they've achieved real and significant age reversal. For that, of course, we need robust, reliable and responsive aging biomarkers.

We're currently looking at several biomarkers, including DNA methylation epigenetic clocks (GrimAge in particular), the frailty index (even though it doesn't seem very responsive), peak exercise capacity, TNF-alpha receptor II, CRP, IL-6, GDF-15 / MIC-1, IGF-1, Cystatin C, NT-proBNP, HGBA1c, and telomere length.

Are there other biomarkers you would recommend we use? And are there 'phenotypic' biomarkers that you would recommend - things like improved libido, darkening / regrowing hair, smoother skin, and the likes?

Would love to hear what you think!
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Comments

  • NickOttensNickOttens Community Manager Barcelona, SpainPosts: 798 admin
    @efoehr, @Polina_veritas, @AlexZhavoronkov, @amoskalev, @poulain, you may have an opinion on this. Which biomarkers should we use to test if teams competing in this competition are achieving significant age reversal?
  • davidsinclairdavidsinclair Posts: 1
    Physical attributes can be tested. In our hands, they seem very responsive to interventions.
    See this paper we have in press at Nat Commun. It's simple and reproducible across labs. There's a website to enter data. http://frailtyclocks.sinclairlab.org/ Preprint is here: https://www.biorxiv.org/content/10.1101/2019.12.20.884452v1
    There is also the glycan age from Gordan Lauc's lab which seems accurate too.
  • NickOttensNickOttens Community Manager Barcelona, SpainPosts: 798 admin
    Thank you for sharing, @davidsinclair!

    @stuartmaudsley, @gatzmon, @Umbertog, @amoskalev, @Barardo, @SWBT, @dani_chronomics, what is your opinion? Which biomarkers do you think we should use to judge teams competing in an XPRIZE competition to reverse aging?

    (More info about this prize design here.)
  • JeanHebertJeanHebert Professor, Neuroscience and Genetics Posts: 5
    The above mentioned markers can be useful, but with the caveat that it is hard to distinguish whether they reflect increased health (or aspects of health) or decreased age. These are separable and need to be distinguished to know whether any treatment is simply affecting health or also age. As the field has known for a long time, there are myriad forms of intracellular and extracellular macromolecular damage (literally hundreds of forms) that accumulate over time. They all likely contribute to the frailty of old age. Reliable markers for aging per se would need to measure the levels of biochemical damage, or at least representative sets of damage that occur to proteins, DNA, lipids, and carbohydrates.
  • NickOttensNickOttens Community Manager Barcelona, SpainPosts: 798 admin
    Thank you for sharing your insights, @JeanHebert!

    @solangemassa, I'm curious what you think about this as well.
  • sureshjsureshj Postdoc fellow Posts: 5
    edited July 18
    I want to add a couple of markers to the list:
    Multiple studies suggest that Ig glycans are markers of aging
    Extracellular vesicles as markers of aging (particularly brain aging).
  • rudihoffmanrudihoffman Chief Financial Engineer Posts: 4
    Hello, Esteemed Colleagues. This is Rudi Hoffman, new to this list. I am a well-informed layman regarding age reversal, not a scientist or researcher like David Sinclair and some of you. The above biomarkers seem to be a good start. May I ask/observe that in addition to the efficacy of the biomarker test, factors like cost, accessibility, and convenience be considered? I had a telomere length test done, it was about $500 bucks and took several months to get results, and these accurately still showed a broad range of results due to the variability of telomeres, I believe.
    And may I say how genuinely thrilled I am about this age-reversal X-Prize initiative, and delighted and humbled I am to be a part of it! I will do my best to pull my weight within the skill-sets I have to contribute.
    Rudi Hoffman
    Port Orange, FL
  • StefaniaStefania Posts: 1
    Age reversal should imply an extended lifespan to me. If someone claims that a "rejuvenation effect" has been achieved, that should mean making a living organism really younger, right? Would it be too simplistic to just apply a treatment to an animal/organism really old, and close to death to see if instead of dying as it was supposed to do <8in a few months maybe), it continues to live?
  • mikeantmikeant Posts: 1
    edited July 20
    In addition to molecular markers it can be worthwhile to consider phenotype markers such as skin aging. As far as I understand skin age can be analyzed with AI to predict age and even potentially detect some diseases; it should also be easy to evaluate as you just need to take photos with consistent lighting -- which is a big plus for trials. In my view, skin age wouldn't make a lot of sense stand-alone (we wouldn't want simple cosmetic products to count as age reversal treatments), yet it could be a useful extra indicator in a composite marker set.

    One company/group that does promising analysis is https://haut.ai/, although perhaps there are others.
  • NickOttensNickOttens Community Manager Barcelona, SpainPosts: 798 admin
    Thank you all for sharing your insights and feedback!

    @rudihoffman, the issue of cost is definitively one we need to consider. Our researcher are looking into that and I expect we'll have some questions for the community on that topic in the next few weeks.
  • rudihoffmanrudihoffman Chief Financial Engineer Posts: 4
    Thank you for your response, Nick. My main contribution to this group will be helping recruit people who are much smarter than I in this topic. I have already reached out to some of these, and will continue this effort to increase collaboration and support.
    Rudi Hoffman
  • NickOttensNickOttens Community Manager Barcelona, SpainPosts: 798 admin
    Thank you for your response, Nick. My main contribution to this group will be helping recruit people who are much smarter than I in this topic. I have already reached out to some of these, and will continue this effort to increase collaboration and support.
    Rudi Hoffman

    Thank you so much! Please feel free to share the link to the community with your contacts or connect them with me by email.
  • NickOttensNickOttens Community Manager Barcelona, SpainPosts: 798 admin
    mikeant wrote: »
    In addition to molecular markers it can be worthwhile to consider phenotype markers such as skin aging. As far as I understand skin age can be analyzed with AI to predict age and even potentially detect some diseases; it should also be easy to evaluate as you just need to take photos with consistent lighting -- which is a big plus for trials. In my view, skin age wouldn't make a lot of sense stand-alone (we wouldn't want simple cosmetic products to count as age reversal treatments), yet it could be a useful extra indicator in a composite marker set.

    One company/group that does promising analysis is https://haut.ai/, although perhaps there are others.

    Absolutely! The company's founder, @nastyahaut, is even a community member.

    Let me add a separate discussion on automated phenotypic assessments.
  • nastyahautnastyahaut Posts: 2
    @mikeant thanks for bringing this up. An idea for an unbiased method using skin imaging - use body skin or hands. These parts are treated with cosmetics at a lesser extent and can be standardized.
    I think biomarkers dynamics and response to intervention can serve as a biomarker itself.
  • RoeyRoey Posts: 157 XPRIZE
    Physical attributes can be tested. In our hands, they seem very responsive to interventions.
    See this paper we have in press at Nat Commun. It's simple and reproducible across labs. There's a website to enter data. http://frailtyclocks.sinclairlab.org/ Preprint is here: https://www.biorxiv.org/content/10.1101/2019.12.20.884452v1
    There is also the glycan age from Gordan Lauc's lab which seems accurate too.

    Thank you, @davidsinclair ! The FRIGHT and AFRAID clocks are just what we're looking for in terms of composite markers, but have only been developed for mice. Would you happen to know if there are similar clocks for human beings?
    We're also exploring the GlycanAge clock for humans at the moment. Thanks again!
  • RoeyRoey Posts: 157 XPRIZE
    JeanHebert wrote: »
    The above mentioned markers can be useful, but with the caveat that it is hard to distinguish whether they reflect increased health (or aspects of health) or decreased age. These are separable and need to be distinguished to know whether any treatment is simply affecting health or also age. As the field has known for a long time, there are myriad forms of intracellular and extracellular macromolecular damage (literally hundreds of forms) that accumulate over time. They all likely contribute to the frailty of old age. Reliable markers for aging per se would need to measure the levels of biochemical damage, or at least representative sets of damage that occur to proteins, DNA, lipids, and carbohydrates.

    True that, @JeanHebert , and thank you for emphasizing the distinction. We're trying to both measure factors that influence lifespan (more related to biological age) and healthspan (more related to general health).
  • RoeyRoey Posts: 157 XPRIZE
    sureshj wrote: »
    I want to add a couple of markers to the list:
    Multiple studies suggest that Ig glycans are markers of aging
    Extracellular vesicles as markers of aging (particularly brain aging).

    Thank you, @sureshj . We're looking into the GlycanAge clock right now, and it does indeed seem promising!
  • RoeyRoey Posts: 157 XPRIZE
    Hello, Esteemed Colleagues. This is Rudi Hoffman, new to this list. I am a well-informed layman regarding age reversal, not a scientist or researcher like David Sinclair and some of you. The above biomarkers seem to be a good start. May I ask/observe that in addition to the efficacy of the biomarker test, factors like cost, accessibility, and convenience be considered? I had a telomere length test done, it was about $500 bucks and took several months to get results, and these accurately still showed a broad range of results due to the variability of telomeres, I believe.
    And may I say how genuinely thrilled I am about this age-reversal X-Prize initiative, and delighted and humbled I am to be a part of it! I will do my best to pull my weight within the skill-sets I have to contribute.
    Rudi Hoffman
    Port Orange, FL

    Hi @rudihoffman . Good to have you here. We're excited and thrilled about this project as well, and truly believe it'll bring about real change!
  • RoeyRoey Posts: 157 XPRIZE
    Stefania wrote: »
    Age reversal should imply an extended lifespan to me. If someone claims that a "rejuvenation effect" has been achieved, that should mean making a living organism really younger, right? Would it be too simplistic to just apply a treatment to an animal/organism really old, and close to death to see if instead of dying as it was supposed to do <8in a few months maybe), it continues to live?

    @Stefania - that's only partly accurate, I'm afraid. While we do want to achieve a rejuvenation effect, if the treatment is being applied close to death when too much damage has been accumulated, we can't expect it to work instant wonders. My guess is that the treatment would reach its best efficacy when given in adulthood or even old age - but before too much damage has been sustained by the body.
  • RoeyRoey Posts: 157 XPRIZE
    mikeant wrote: »
    In addition to molecular markers it can be worthwhile to consider phenotype markers such as skin aging. As far as I understand skin age can be analyzed with AI to predict age and even potentially detect some diseases; it should also be easy to evaluate as you just need to take photos with consistent lighting -- which is a big plus for trials. In my view, skin age wouldn't make a lot of sense stand-alone (we wouldn't want simple cosmetic products to count as age reversal treatments), yet it could be a useful extra indicator in a composite marker set.

    One company/group that does promising analysis is https://haut.ai/, although perhaps there are others.

    Thank you, @mikeant ! We're definitely looking into that.
  • RoeyRoey Posts: 157 XPRIZE
    nastyahaut wrote: »
    @mikeant thanks for bringing this up. An idea for an unbiased method using skin imaging - use body skin or hands. These parts are treated with cosmetics at a lesser extent and can be standardized.
    I think biomarkers dynamics and response to intervention can serve as a biomarker itself.

    Thank you, @nastyahaut . Could we interview you on this method? We would love to learn more about it.
  • JeanHebertJeanHebert Professor, Neuroscience and Genetics Posts: 5
    Roey wrote: »
    Stefania wrote: »
    Age reversal should imply an extended lifespan to me. If someone claims that a "rejuvenation effect" has been achieved, that should mean making a living organism really younger, right? Would it be too simplistic to just apply a treatment to an animal/organism really old, and close to death to see if instead of dying as it was supposed to do <8in a few months maybe), it continues to live?

    @Stefania - that's only partly accurate, I'm afraid. While we do want to achieve a rejuvenation effect, if the treatment is being applied close to death when too much damage has been accumulated, we can't expect it to work instant wonders. My guess is that the treatment would reach its best efficacy when given in adulthood or even old age - but before too much damage has been sustained by the body.

    Rejuvenation should indeed imply making an organism younger, @Stefania and @Roey. And Roey, you are right, rejuvenation is difficult to achieve especially the older one gets given the current predominant way of thinking about how to achieve rejuventation, which is by using pharmacological or biologic treatments (with this way of thinking it is indeed unrealistic to expect reversal of sufficient damage). On the other hand, the field of regenerative medicine will eventually provide the means of making an old person young again through cell and tissue replacements, a perspective all too often ignored by the anti-aging field. Such replacement approaches could/will reverse damage even in very old individuals, so Stefania's point should I think be seriously considered.
  • stephanielstephaniel Owner Posts: 19 ✭✭
    edited July 22
    I'd like to add that some additional potential age markers could be CoQ10 levels (efficient activity of mitochondria) and, especially for women, bone density scores.

    Also, editing to add: There was a study in 2018 that showed correlation of menopause age with diet to some degree (oily fish and fresh legumes were associated with later menopause by 3 and 0.9 years per daily serving, respectively, while refined carbs were associated with earlier menopause by 1+ year per daily serving). Vitamin B6 and zinc intake also correlated with later menopause. Source: https://jech.bmj.com/content/72/8/733 So maybe age of menopause could be used as a long-term marker of anti-aging success as well.
  • marz62marz62 Seattle, WAPosts: 120 ✭✭✭
    Okey dokey...I'm going to jump right in with some 'first thoughts'...

    First, to determine true age reversal (or 'rejuvenation') we would need to pre-establish and measure/assess the key variables/biomarkers for each individual to be tested (prior to receiving the 'treatment', whatever it be). This will likely mean (at the least) some quantification/quantization of said biomarkers.

    For example, let us suppose that a decrease in the number of senescent cells (per tissue type, or 'ageotype' [i.e., kidneys, liver, immune system, metabolism; M. Snyder et al, Stanford Univ.] parameter) is our biomarker of 'age reversal'...we therefore must a priori quantify these cells (a senescent 'baseline' if you will) in a 'normally aged' person, then, following the treatment (and monitoring for a specified period of time to determine how lasting the rejuvenation effect is)...determine the new senescent cell count, etc.

    It would also be crucial to have data from the general population regarding the average amount of senescent cells that a person (non-obese, non-diabetic, non-cancerous, non-arthero-sclerotic, etc.) accumulates by age 50/55 (as an example age)...similar to a 'Hayflick' limit (i.e., cell divisions prior to cell death/senescence) ...or similar perhaps to a random mutation rate per cell division [Tomasetti and Vogelstein, 2018/2019; they cite eight mutations on average per cell division].

    Basically: we need numbers for each biomarker, so, the biomarker must e quantifiable (not to make too obvious a point).

    I will add some other biomarker ideas in another comment.
  • marz62marz62 Seattle, WAPosts: 120 ✭✭✭
    edited July 23
    Some candidate bio-markers:
    > Loss of Epigenetic marks -- as we age we lose key epigenetic marks that control the expression of genes; the most common cited example is the loss of methylation marks (generally, these are gene 'silencing', though not always) on chromatin; the loss of these gene silencing methyl groups (e.g., on oncogenes) is associated with general cell/tissue/organ aging. There are other epigenetic marks (e.g., acetyl, phosphoryl groups), but methyl groups seem to be the longest lasting and most impacting (and are, in fact, inherited, up to at least three generations). We would need a reliable quantification method here (forensic science methods for doing this [to determine corpse age] are evolving rapidly).

    >Loss of B cell (genomic) diversity - as we age, our B cells' Immunoglobulins (Ig) exhibit less diversity in their heavy and light chain amino acid sequences (this is associated with a failing immune system, one that is less able to successfully mount an immune defense against a random pathogen); this random production of diverse B-cell genomes (and thus Ig diversity) takes place in the 'germinal centers' of lymph nodes (light and dark zones) where diverse sequences are presented to key T cells for 'evaluation' and selection or (most often) destruction. We would need to calculate a 'normal' or optimal rate of B cell Ig presentation (and/or a metric for normal/healthy H/L chain diversity) -- at specific benchmark ages -- and compare these metrics to an aged geno/phenotype (and these to a 'rejuvenated' phenotype, etc.).

    > Circadian clock transcription factors (e.g., BMAL, CLOCK, and their respective genes BMAL, CLOCK; other key circadian genes: per, cry ) in astrocytes ('supportive' brain cells). It has been speculated for some time that the dysregulation of the UPR (unfolded protein response) and the concomitant build-up of un/misfolded proteins (and decrease in protein degradation) in cells contributes mightily to cell aging. It is our circadian clocks that regulate this protein folding/cycling. Recent research (Brancacci et al, 2019) has shown that the periodicity ('rhythmic activity') of Circadian clocks (in astrocytes) shortens as these cells age (and probably impact nearby neurons, which are 'tuned' and pruned by astrocytes and feedback information to astrocytes) but that the normal periodicity of astrocyte circadia can be 'rescued' by ablating certain circadian genes (cry, per).

    Note: I speculate here that neurons could be bio-engineered (via a viral CRISPR cassette) to release glutamate (an excitatory neurotransmitter that engages in feedback with neural [and probably astrocye] circadian clock genes and transcription factors) more slowly, thus lengthening the periodicity of a cell's rhythmic activity...and slowing down the aging cellular 'clock'
  • RoeyRoey Posts: 157 XPRIZE
    stephaniel wrote: »
    I'd like to add that some additional potential age markers could be CoQ10 levels (efficient activity of mitochondria) and, especially for women, bone density scores.

    Also, editing to add: There was a study in 2018 that showed correlation of menopause age with diet to some degree (oily fish and fresh legumes were associated with later menopause by 3 and 0.9 years per daily serving, respectively, while refined carbs were associated with earlier menopause by 1+ year per daily serving). Vitamin B6 and zinc intake also correlated with later menopause. Source: https://jech.bmj.com/content/72/8/733 So maybe age of menopause could be used as a long-term marker of anti-aging success as well.

    @stephaniel - thank you! We'll look into these biomarkers.
  • RoeyRoey Posts: 157 XPRIZE
    JeanHebert wrote: »
    Roey wrote: »
    Stefania wrote: »
    Age reversal should imply an extended lifespan to me. If someone claims that a "rejuvenation effect" has been achieved, that should mean making a living organism really younger, right? Would it be too simplistic to just apply a treatment to an animal/organism really old, and close to death to see if instead of dying as it was supposed to do <8in a few months maybe), it continues to live?

    @Stefania - that's only partly accurate, I'm afraid. While we do want to achieve a rejuvenation effect, if the treatment is being applied close to death when too much damage has been accumulated, we can't expect it to work instant wonders. My guess is that the treatment would reach its best efficacy when given in adulthood or even old age - but before too much damage has been sustained by the body.

    Rejuvenation should indeed imply making an organism younger, @Stefania and @Roey. And Roey, you are right, rejuvenation is difficult to achieve especially the older one gets given the current predominant way of thinking about how to achieve rejuventation, which is by using pharmacological or biologic treatments (with this way of thinking it is indeed unrealistic to expect reversal of sufficient damage). On the other hand, the field of regenerative medicine will eventually provide the means of making an old person young again through cell and tissue replacements, a perspective all too often ignored by the anti-aging field. Such replacement approaches could/will reverse damage even in very old individuals, so Stefania's point should I think be seriously considered.

    @JeanHebert - true that. It's a fine balance, and it is very true that the older our cohort, the more likely we are to see some improvement in aging biomarkers taking place.
  • RoeyRoey Posts: 157 XPRIZE
    Thank you, @marz62 ! We'll look into these biomarkers as well.
  • NickOttensNickOttens Community Manager Barcelona, SpainPosts: 798 admin
    @james7, @nic, @HarishHandral, @Felix_Werth, @Vatrak, which biomarkers would you recommend?
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