Biomarkers

JessicaYoon

In order to make Phase 2 clinical trials more affordable, we will optimize the number and type of biomarkers for the competition, with at least two that reflect clinical outcomes.

These may include:

• Blood-based biomarkers reflecting the immune system function. Costs likely to range from $25 for ELIZA to $600 for measuring cell populations via mass cytometry.
• Cosmetic youthfulness (hair density and color, skin tone). Can be collected with a smartphone camera.
• Cardiopulmonary Exercise Test (CPET): $700 / visit. May be replaced with remote monitoring devices such as HRV Elite's Corsense, for $165 / device.
• Neurocognitive assessments. Can be conducted online.
• Custom-made frailty index. For self-reporting.
• DNAm epigenetic clocks. $200 / sample.

Please share your feedback on biomarkers here!

NickOttens

@ymedan, @davidsinclair, @JeanHebert, @sureshj, @rudihoffman, @Stefania, @nastyahaut, @stephaniel, @marz62, since you weighed in on our general discussion about aging biomarkers, I would like to request your feedback here as well.

If we're doing an XPRIZE Age Reversal that is focused on the immune system (more info here), would that change your recommendation on which biomarkers to use?

What do you think about the ones listed by @JessicaYoon above?

ymedan

@NickOttens Thanks. I am not sure that I understand the scope (size, age groups, duration, endpoints) of such trials. Could you please clarify? These parameters impact the cost of such a study.
I am also confused about the use of the term "age reversal". Does the immune system have an age clock marker? Could it be that a person will have a robust immune system but other epi/genetic markers will indicate that he is older or younger than the chronological age indicates?

IMHO, aging is a metabolic process rather than an immunologic process. Immune deficiency may be an outcome, not a root cause. I am sure that @marz62, @davidsinclair and others are more knowledgeable than I am in commenting on this. I am just practicing/experiencing aging as we speak

NickOttens

ymedan wrote: »

@NickOttens Thanks. I am not sure that I understand the scope (size, age groups, duration, endpoints) of such trials. Could you please clarify? These parameters impact the cost of such a study.
I am also confused about the use of the term "age reversal". Does the immune system have an age clock marker? Could it be that a person will have a robust immune system but other epi/genetic markers will indicate that he is older or younger than the chronological age indicates?

Nothing is set in stone yet, but, in order to reduce the cost of Phase 2 clinical trials, we're thinking of 3- to 12-month long trials, with 70+ years olds, and cohorts of 30-50 per competing team.

I'll have to ask @Roey if he can answer your second question.

JeanHebert

@NickOttens, @ymedan While an immune system focus may result in immune health benefits with possible reduced age-related markers in blood-based biomarkers (including epigenetics of circulating immune cells), which is a good thing, it seems much less likely that with this focus we are still talking about "age reversal". Reduced frailty and a return to more youthful cognition and cosmetics (as reasonable markers listed above by @JessicaYoon) are less likely to be significantly affected if at all. @NickOttens The focus on the immune system certainly makes political sense as you argue, but is I'm afraid going to limit the impact of the competition.

sureshj

I agree with @JeanHebert. While focusing on the immune system is a great idea, we may not achieve neural and cognitive reversal. I suggest focusing on a pathway or genes (marker) that is common to multiple systems (for example, the immune and nervous systems).

rudihoffman

I am following the discussion re: immune system markers with interest. I agree with @JeanHebert and @NickOttens, @ymedan that immune system alone is not really "Age Reversal." Is it not accurate to say we want a GOLD STANDARD of ACTUAL SENSESCENCE REVERSAL? This would include the immune system, but not be limited to this. If we are looking for maximal societal impact, a prize, or even clear cut documentation, showing "hey, we improved immune system response, or even reversed senescent immune response" is likely to be "So what?"
The real prize is actually reversing pretty much ALL biomarkers of aging...both the prize and what we want to have happen is real aging reversal. I know this is much harder to do and have metrics on, but I submit that this prize is one of the most significant in human history. True age reversal will be a watershed moment for the species...and we will see it in our lifetime!
Btw, in an aside about mechanics of this discussion board, I just discovered the functionality that there are suggestions for the names that pop up upon typing the first few letters of the participant.
Very cool!
Rudi Hoffman rudi@rudihoffman.com

NickOttens

Thank you for your comments!

Our thinking is that any rejuvenation of the immune system will necessarily involve rejuvenation, i.e. age reversal, of the whole body. We're testing that theory, though, so your comments are most welcome. Let's get some more input!

JeanHebert

@NickOttens, , @Roey, @ymedan, @sureshj Although not for the faint of heart, true age reversal will be achievable before long due to advances in regenerative medicine, which will allow for wholesale replacements of cells, tissues, and organs of the body with damage-free lab-grown ones. Such replacements are already being used in humans to treat injuries or congenital deficits (I refer you, for example, to the wonderful work being done by Anthony Atala's group at Wake Forest). Even for the brain, progressive cell replacement without a loss of self-identity should be possible (Hebert and Vijg, 2018, Trends in Neuroscience, v41 p267-279). We're obviously not there yet and clinical trials wouldn't happen for quite some time, but in terms of truly reversing aging this approach (unlike most others proposed) will eventually work, not just to make us healthier in old age, but to reverse all forms of macromolecular damage and actually make us young again ...perhaps all we need is a bold prize to whoever can make the most progress in this direction.

ymedan

@NickOttens, @Roey, @jeanhebert, @sureshj
I am not so sure that organ replacement/regeneration alone will create that age reversal magic. "Bag of Parts" medicine has not solved the burden of chronic diseases, including cancer. Will regenrating the Pancreas will cure Diabetes Type 2? Perhaps rejuvenating/diversifying the gut microbiome will do that faster than regenerating an organ.
I am inclined to expect that @davidsinclair will come up with a way for methylating the DNA, which will reverse the age. In a way, this may induce regeneration (if the microbiota will not null it) but not locally but rather systematically. The body is a closed loop system, not a collection of cells and organs.

JeanHebert

@NickOttens, @Roey, @jeanhebert, @sureshj When considering age reversal, if we continue to ignore the myriad forms of covalent damage that occur to all classes of macromolecules as we age (which have been described by biochemists for decades, and a partial list of which is nicely described by Caleb Finch in his Longevity, Senescence and the genome book), then it will be difficult if not impossible to reverse aging. Our bodies are mostly extracellular matrix and connective tissue, where protein and carbohydrates turnover slowly if at all. Case in point, when young hematopoietic stem cells are transplanted in old mice (even though their genome, epigenome, mitochondria etc are young going in), they behave more like old stem cells. So targeting methylation, mitochondria, metabolic pathways, or other popular targets will have little effect on age reversal (never mind that implementing changes to these targets in the whole organism, especially if combining targets, without deleterious side effects that outweigh the benefits is difficult to imagine - will we use a battery of drugs and viral vectors and expect benefits without side effects?). Meanwhile, every part of the body, including the pancreas has been transplanted successfully in humans (hearts, lungs, kidneys, intestines, bladders, arms, legs, faces...literally every part of the body except the brain). So replacements are not the problem - they work and allow people to live longer everyday. The problem is the current limited source of organs and body parts, which are usually from deceased donors (except for kidneys and a few others). But the field of regenerative medicine has been making increasingly sophisticated and functional lab grown organs that in some cases like the bladder and a handful of other examples are being transplanted - and are functioning - in patients. These lab-grown organs and tissues are free from the myriad forms of intra and extracellular age-related damage. Of course, until we can replace most organs with lab-grown ones, it will not be worth attempting rejuvenation, because I agree the body is in many ways a closed loop. But once we have enough of these organs available, which seems inevitable given the pace of progress in this field, then we will be able to truly erase age-related damage.

Roey

ymedan wrote: »

@NickOttens Thanks. I am not sure that I understand the scope (size, age groups, duration, endpoints) of such trials. Could you please clarify? These parameters impact the cost of such a study.
I am also confused about the use of the term "age reversal". Does the immune system have an age clock marker? Could it be that a person will have a robust immune system but other epi/genetic markers will indicate that he is older or younger than the chronological age indicates?

IMHO, aging is a metabolic process rather than an immunologic process. Immune deficiency may be an outcome, not a root cause. I am sure that @marz62, @davidsinclair and others are more knowledgeable than I am in commenting on this. I am just practicing/experiencing aging as we speak

@ymedan - we are still debating the scope of these trials, but they are very unlikely to include a cohort larger than 100 participants. Participants ages will probably be 60-70, the duration will not be longer than one year, and the endpoints will depend on the body systems we'll require the participants to rejuvenate, plus epigenetic clocks as a general marker of 'biological age' (which is the best we have right now).
As for the term "age reversal" - it's better to say "rejuvenation". The immune system does not have a clear aging clock, but we do know of several immune parameters that decline throughout aging, and if we can rejuvenate the system so that an old person has the same parameters as a young person (CRP & IL-6 levels, blood cells populations, immune response to vaccination, etc.) then that would be enough evidence of a "rejuvenation" effect for us. Since teams will receive bonus points for also rejuvenating the cardiovascular and central nervous systems, any treatments that does all three and reduces a person's biological age as measured by the epigenetic markers, could conceivably be considered "age reversal".

ymedan

@Roey Thank you. I highly recommend measuring NK cells load (inate immune system function). There is a symposium dedicated to that https://innate-killer.com/ next week.
I would not say "age reversal" but rather "aging slowdown". Unless you know something that I don't know about mortality, we are all bound to die, no matter how much we will reverse our age.