Aging Biomarkers and Health Measures

Dear GRG Member,

About a year or so ago I sent a request to GRG members asking for input about aging biomarkers and other health measures relevant to aging. This was before some of you joined.

Below are notes and related comments sent to our forum and otherwise collected, along with a quick note about the small pilot study format we’re now using and further formalizing for humans.

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For the purpose of testing in HUMANS
Testing among small group — Aging biomarkers and health measures
Pilot/beta/small human trial format — a “practical, small, informal, fast track, cautious and low risk, MD monitored and controlled” method with aging biomarkers and biological/health measures, conducted by a small group of associates.

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Responses to request for aging biomarkers and health measures sent to the GRG email discussion forum and a few others collected:

We want parameters that don’t have daily/weekly/monthly/yearly fluctuation

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Theranos labs
http://ift.tt/1ciByV9

http://ift.tt/1COJinx
LabCorp and Quest

SomaLogic.com
See SSM-002-Rev-2-SOMAscan-Technical-White-Paper-3-7-15.pdf
Renamed in this folder
2014SomaScanWhitePaper_SSM-002-Rev-2-SOMAscan-Technical-White-Paper-3-7-15.pdf
http://ift.tt/1ciBzIy

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James P. Watson MD and Vinci Giuliano
HRV

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Florence Comite MD
HbA1C, if 5 or less correlates with longevity.

And HDL, an older biomarker, if at the higher end of range, also correlates with longevity.

There are others however most are variable and should be judged in the context of many other factors, family history, genomics, sleep, nutrition, exercise, other metabolomics.

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Per neuro-endocrinologist with patient experience and high credentials
Q: Usually what hormone assays?
Which lab test company do you use for hormone assays?
A: Labcorp or Quest

Are there hormone assay panels you would suggest?
Assay all pituitary hormones
don’t usually anterior oxy and vasopresin
prolactin
leutinizing hormone
FSH
growth hormone
IGF-1
thyroid stim hormone
ACTH (adrenocorticotropic hormone)

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Thomas Coote
PHYSICAL: 1) Muscle strength 2) Short Physical Performance Battery
CHEMICAL: 1) Serum albumin 2) IL-6 3) Urea 4) Eotaxin (my idea)
MENTAL/COGNITIVE: 1) MMSE
PROTEOMIC: 1) Plasma transferrin
GENETIC: 1) miRNA expression by QrPCR (several candidates).

. . . obviously ease of analysis and cost of analysis would have to be considered.
A couple I have rejected are Systolic BP and CRP as they are quite variable and may change due to non-age related circumstances.

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Bill
Theranos panel
http://ift.tt/1ciByV9

grip strength
Inflammation markers
IL-6, IL-10, IL-17, TNF tumor necrosis factor
Glucose tolerance?
IGF11

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John
Lipofuscin accumulation (can this be tested?)
in neurons
– Weight
– Resting blood pressure
– FEV1
– max grip strength each hand
– number of push ups in 60 seconds
– number of chin ups in 60 seconds

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Sven Bulterijs — HAS
Hallmarks of Aging Score
http://ift.tt/1ciByVc

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David Cross
Additional Biomarkers of Aging for consideration:

–Pulmonary function (‘Pulmonary Age’)–via Spirometry
–Arterial Stiffness–via Sphygmocor
–Measure of cognitive function–‘CNS Vital Signs’ is one option

–Are there measures of Stem Cell health & functionality (e.g., total #s, regenerative capacity, mobilization, etc.) that can be used as a tangible Biomarker of Aging?

–Telomere Length: Maria Blasco’s Life Length lab measures (in PBMCs) not only median telomere length but also the % of ‘critically-short’ telomeres, which is actually the more important measure, as per Harley, Greider, et.al., it takes only one critically-short telomere to throw a cell into senescence.

–Immune measure: The UCLA Clinical Immunology Laboratory at the Geffen School of Medicine (Tony Butch/Najib Aziz) performs a “Flow T-cell subset Analysis” which measures the % of senescent CD8+/CD28- T-cells, which per Harley/Andrews/Blasco is considered a very important “biomarker of immune aging.”

The research of Rita B. Effros (UCLA) over many years demonstrates that CD28 T-cell senescence is a major factor in immunosenescence, which is of course critical to aging, and “inflammaging,” including the finding that senescent CD28- T-cells secrete and increase the circulation of the pro-inflammatory cytokine TNF-alpha (Effros 2011, 2013). Her research plus that of several others demonstrates that the % of CD28- T-cells contributes to a number of age-related degenerative diseases, including rheumatoid arthritis

(Weyand & Gorozny 2014), “early atherosclerotic damage in rheumatoid arthritis patients” (Gerli, et.al. 2004), and “increased cardiovascular risk in diabetes mellitus” (Giubilato, et.al. 2011), among others.

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Josh Mittledorf blog:
Luigi Fontana has experience in biomarkers
I suggest you contact Luigi Fontana at Wash U in St Louis for this. He has
lots of experience with age markers in humans.
lfontana@dom.wustl.edu

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Vince Giuliano
Resting heart rate
avg one hour before going to sleep and waking
smartwatch
http://ift.tt/1yu34by
Vince
http://www.Mybasis.com
transfer data to smartphone
go another step

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Jim Watson said this re Quercetin and Dasatinib. Otherwise applies?
Before everyone goes out and buys Quercetin and Dasatinib, it would be wise to conduct an IRB-approved trial for these two agents with specific age-related phenotypes as primary endpoints.
This could include one or more of the following conditions:

1. Presbyopia (pesbyopia?)- This could easily be measured with eye exams by a “blinded examiner” (no pun intended) – age-related visual changes can be measured by diopter changes
2. Prebycusis – This could also be easily measured with hearing tests. Age-related hearing loss is manifested by a characteristic high frequency conduction hearing loss
3. Decline in LVEF – This could easily be measured with echocardiography
4. Vascular reactivity – This could easily be measured with nitroprusside-induced changes in BP and arterial waveforms on A-line
This could also be done with flow-mediated dilation (FMD)
5. Skin aging – this could easily be measured with a skin biopsy – this could be done with beta-galactosidase staining and p16 staining
6. Muscle aging – this could easily be measured with a muscle biopsy – this could be done with beta-galactosidase staining and p16 staining
7. Liver aging – this could easily be measured with a liver biopsy with beta-galactosidase staining and p16 staining

I think it is time to do this under an IRB.

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Harold Katcher
For plasma transfer

Blood tests
Cytokines and antibodies (some may not be feasible the first 8 are required, 11 is highly preferred as are 11 – 15.
1. CRP
2. TNF-alpha
3. TGF-beta
4. IL-10
5. IL-6
6. IL-1
7. Soluble TNF-receptor (type I)
8. Soluble TNF-receptor (type II)
9. Autoantibodies/ – against a variety of factors (RF, ANA, anti-thyroid Ab)
10. Immune complexes
11. BNP (brain natriuretic protein)
12. granulocyte colony-stimulating factor (G-CSF)
13. CCL-11 (‘eotaxin’)
14. MIG (monokine induced by gamma interferon)
15. macrophage colony-stimulating factor (M-CSF)
16. Exosomes RNA content (if only – would require ‘deep sequencing’)

Lymphocytes
1. FACS for distribution of b-cells, t-cells (CD-3, CD-28) CD4+, CD25+, CD8+ CD28+
2. P16INK4a expression in T – cells

Metabolism
1. Insulin and glucose
2. IGF-1
3. Lipids and apolipoproteins (apo A1, apoB, apoC, apoE)
4. Testosterone (free)
5. Hemoglobin concentration
6. DHEA
7. Free T3
8. Sedimentation rate

Other factors (cellular factors also in the blood (or liver, skin – we need an earlier marker than HSC rejuvenation)
1. Telomerase
2. Telomere length
3. MMP-9
4. miRNA expression profiling (qPCR)

Safety labs
1. CBC
2. LFT’s
3. BUN and creatinine

Functional Testing
1. Cognitive ability/memory testing (computerized?)
2. Physical strength, Up and Go
3. Presbyopia
4. FEV
5. Age-specific quality of life scale

Senescent Symptoms to be photographed (with a ruler alongside)
1. Balding patterns
2. Age spots
3. Senile fold (earlobe)

plasma exchange
GRG
grip strength, total blood hemoglobin, TUG tests (time of up and go)- and maybe some psychological tests where the aged score appreciably worse than younger people

From 4/4/2015 message
No single determinant in the blood,
there are age dependent changes in TNF receptors (type II),
hemoglobin concentrations,
hematocrit etc..
There is the very well known increase in inflammatory cytokines,
and the increase in CCL-11 (which Villeda showed caused cognition deficits and a down-turn in neurogenesis, as did aging itself, which caused a concomitant increase CCL-11 “eotaxin” concentration).

However that’s the ‘beauty’ of using human subjects – changes in age phenotype will become visible over time to other humans.
Tests of speed of perception, tests of short-term memory.

We need not confine ourselves to blood tests.

Tests of skin thickness and structure are possible with the relatively non-invasive ‘punch’ skin biopsies.

We are pretty good at guessing age – I think if we add the computer generated parameters -we can be even better.
Such signs as hairline recession are not apparent in animals but are in men.
Age spots – the appearance and disappearance of which are not taken into account would be a good indicator of physiological age, certainly their disappearance would be very strong evidence – are measures not possible in animals..

Best of course would be the change in epigenetic marks – such as DNA cytosine methylations- which Horvath showed to be an accurate indicator of chronological age – and see whether these patterns change to be more like that of a younger organisms.

And also of importance would be to isolate stem cells and check the ratios of age-related gene’s transcription rates.
So if the ratio of a specific DNA/chromatin repair enzymes to specific inflammatory cytokine transcription is at a certain level we can tell what life-stage the organism is in, I think.
So I agree the best indicators of age are physical appearance and function – and those are the parameters I will measure to establish that rejuvenation has occurred.

Harold Katcher
Sent in private message, permission given to forward GRG
So I don’t see any reason why a bunch of parameters can’t be monitored at the same time.
Since except possibly for epigenetic changes in DNA that are age-predictive
and perhaps tissue and age specific transcriptional profiles (including miRNAs)
there are no age-biomarkers (though both the epigenetic marking of cells and transcriptional profiles would both contribute to discerning an effect.
So perhaps the better approach is to see the effect on the diseases of aging – particularly on the underlying processes of
atheroma growth,
heart performance and
why not tests of mental agility and physical performance as well?
Luminosity-like test could be given to determine visual and other processing speeds – test of memory are easy to perform.
Also other common markers of aging (like balding – it might seem trivial but a reversal of balding would be impressive) and
disappearing age spots (photographed) would also contribute to a narrative of rejuvenation.
The changes are likely to take weeks (and reason to suppose even longer for the immune system),
but we could see if such underlying causes of aging diseases such as
presence of senescent cells,
chronic low-grade inflammation with simple blood tests.
Skin biopsies could demonstrate changes in
skin thickness and composition – properties known to change with aging.
The additional costs would be modest, but they could make all the difference in establishing that it works.

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Paul Wakfer
. . . the lab animal to human conversion factor relative to metabolic rate differences. For mice this computes to about 7.3, so the human equivalent dose would only be 3500/7.3 = 480 mg for a 70 kg human. This is an easily available dose and about what I and Kitty have been getting proportionate to our weights (62 and 50 kg respectively) for well over a decade now.

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J Pedro Magalhaes
developed the Digital Ageing Atlas, a new portal of age-related changes at different biological levels that might be useful for your purposes:
http://ageing-map.org/
For gene expression biomarkers please see:
http://ift.tt/1ciBzIC

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DNA methylation per Steve Horvath — This has been questioned by one or two experts I have spoken with.

Steve Horvath

Steve,
I have noticed that there have been several interesting posts on biomarkers of aging.
I would be grateful if you could post the following recent article that provides a case study of how the epigenetic clock can be used to detect an accelerates aging effect in the livers of obese subjects.

http://ift.tt/1ciBzbs

Obesity accelerates epigenetic aging of human liver

Abstract
Because of the dearth of biomarkers of aging, it has been difficult to test the hypothesis that obesity increases tissue age. Here we use a novel epigenetic biomarker of aging (referred to as an “epigenetic clock”) to study the relationship between high body mass index (BMI) and the DNA methylation ages of human blood, liver, muscle, and adipose tissue. A significant correlation between BMI and epigenetic age acceleration could only be observed for liver (r = 0.42, P = 6.8 × 10−4 in dataset 1 and r = 0.42, P = 1.2 × 10−4 in dataset 2). On average, epigenetic age increased by 3.3 y for each 10 BMI units. The detected age acceleration in liver is not associated with the Nonalcoholic Fatty Liver Disease Activity Score or any of its component traits after adjustment for BMI. The 279 genes that are underexpressed in older liver samples are highly enriched (1.2 × 10−9) with nuclear mitochondrial genes that play a role in oxidative phosphorylation and electron transport. The epigenetic age acceleration, which is not reversible in the short term after rapid weight loss induced by bariatric surgery, may play a role in liver-related comorbidities of obesity, such as insulin resistance and liver cancer.

Citation.
Steve Horvath, Wiebke Erhart, Mario Brosch, Ole Ammerpohl, Witigo von Schönfels, Markus Ahrens, Nils Heits, Jordana T. Bell, Pei-Chien Tsai, Tim D. Spector, Panos Deloukas, Reiner Siebert, Bence Sipos, Thomas Becker, Christoph Röcken, Clemens Schafmayer, and Jochen Hampe
Obesity accelerates epigenetic aging of human liver
PNAS 2014 : 1412759111v1-201412759.

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Another source (I don’t recall)
Problems if can’t stand on one leg > 20 sec.
Is how long can a person can stand on one leg an indicator?

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Wound healing. How to test?

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MRI
view/measure brain calcification

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Evaluate with an electron microscope?

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Tom Johnson Paper
http://www.sciencedirect.com/science/article/pii/S0531556506002865

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Someone once commented that an experienced geriatrician can watch a patient walk down a hall and gauge their health

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A friend remarked that over his career a Midwestern doctor asked his patients “How are you?”. The ones with a more positive reply tended to live longer and in better health.

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3D Face Scan (Reveals Biological Age Better Than A Blood Profile)
see How Old Are You 3D Face Scan Reveals Biological Age Better Than A Blood Profile.html
Source: Chen W, Qian W, Wu G, et al. Three-dimensional human facial morphologies as robust aging markers. Cell Research. 2015.
Link to the article:
http://ift.tt/1IRAu5e

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About Johnny Adams

My full-time commitment is to slow and ultimately reverse age related functional decline to increase healthy years of life. I’ve been active in this area since the 1970s, steadily building skills and accomplishments. I have a good basic understanding of the science of aging, and have many skills that complement those of scientists so they can focus on science to advance our shared mission. Broad experience Top skills: administration, management, information technology (data and programming), communications, writing, marketing, market research and analysis, public speaking, forging ethical win-win outcomes among stakeholders (i.e. high level "selling"). Knowledge in grant writing, fundraising, finance. Like most skilled professionals, I’m best described as a guy who defines an end point, then figures out how to get there. I enjoy the conception, design, execution and successful completion of a grand plan. Executive Director Gerontology Research Group (GRG). Manages Email discussion forum, web site, meetings and oversees supercentenarian (oldest humans, 110+ years) research. CEO / Executive Director Carl I. Bourhenne Medical Research Foundation (Aging Intervention Foundation), an IRS approved 501(c)(3) nonprofit. http://www.AgingIntervention.org Early contributor to Supercentenarian Research Foundation. Co-Founder Geroscience Healthspan Forum. Active contributor to numerous initiatives to increase healthy years of life. Co-authored book on conventional, practical methods available today to slow the processes of aging – nutrition, exercise, behavior modification and motivation, stress reduction, proper supplementation, damage caused by improper programs, risk reduction and others. Fundamental understanding of, and experience in the genomics of longevity (internship analyzing and curating longevity gene papers). Biological and technical includes information technology, software development and computer programming, bioinformatics and protein informatics, online education, training programs, regulatory, clinical trials software, medical devices (CAT scanners and related), hospital electrical equipment testing program. Interpersonal skills – good communication, honest, well liked, works well in teams or alone. Real world experience collaborating in interdisciplinary teams in fast paced organizations. Uses technology to advance our shared mission. Education: MBA 1985 University of Southern California -- Deans List, Albert Quon Community Service Award (for volunteering with the American Longevity Association and helping an elderly lady every other week), George S. May Scholarship, CA State Fellowship. BA psychology, psychobiology emphasis 1983 California State University Fullerton Physiological courses as well as core courses (developmental, abnormal etc). UCLA Psychobiology 1978, one brief but fast moving and fulfilling quarter. Main interest was the electrochemical basis of consciousness. Also seminars at the NeuroPsychiatric Institute. Other: Ongoing conferences, meetings and continuing education. Aging, computer software and information technology. Some molecular biology, biotech, bio and protein informatics, computer aided drug design, clinical medical devices, electronics, HIPAA, fundraising through the Assoc. of Fundraising Professionals. Previous careers include: Marketing Increasing skill set and successes in virtually all phases, with valuable experience in locating people and companies with the greatest need and interest in a product or service, and sitting across the table with decision makers and working out agreements favorable to all. Information Technology: Management, data analysis and programming in commercial and clinical trials systems, and bioinformatics and protein informatics. As IT Director at Newport Beach, CA based technology organization Success Family of Continuing Education Companies, provided online software solutions for insurance and financial professionals in small to Fortune 500 size companies. We were successful with lean team organization (the slower moving competition was unable to create similar software systems). Medical devices: At Omnimedical in Paramount CA developed and managed quality assurance dept. and training depts. for engineers, physicians and technicians. Designed hospital equipment testing program for hospital services division. In my early 20’s I was a musician, and studied psychology and music. Interned with the intention of becoming a music therapist. These experiences helped develop valuable skills used today to advance our shared mission of creating aging solutions.
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