15 replies to this topic

[Logic]

In the most complete tally yet, scientists have identified nearly 1,500 genes that are connected to how we age
 
Almost every process in our body changes, however quickly or slowly, as we age. And it’s not just genes that are affected by aging, but the ways we live our lives: the things we’re exposed to, the things we eat and how much we exercise among them.
That’s why pinpointing the genes involved in this complex process is a formidable challenge. So far, researchers searching for aging-related genes have focused on identifying parts of the genome connected to specific aging diseases, including inherited disorders like progeria and chronic conditions such as cancer and heart disease.
Now, in a study published in Nature Communications, a group of scientists have pooled the list of genes that change with age and have come up with the most complete list yet of genes involved in aging. Starting with a group of six European studies involving 14,983 people ranging in age from their 40s to 70s, they analyzed blood samples and documented which genes changed in activity—by turning on or off—over time. While previous studies compared the genes themselves to find out which genes differed among people who lived longer and those who did not, Andrew Johnson, the study’s senior author from the Division of Intramural Research at the National Health, Lung and Blood Institute, says they focused on the activity of the genes instead to get a better picture of which genes are changing with age. To measure that, they focused on RNA, the genetic product that our genes produce when they’re active.
MORE: Longevity
“RNA is quite dynamic, since it’s responsive to processes in our tissues and cells,” he says. “If we get sick, say with the influenza virus, or, in this case, if we get old, and we’ve had a more challenging lifestyle or been exposed to things in the environment, our RNAs react and can be found at different levels.”
Indeed, what they found among the nearly 1,500 genes they identified this way as linked to aging were some that have already been known to contribute to the process, as well as new ones that open up novel research opportunities. Among these are genes associated with compounds, called glycosaminoglycans, that are involved in wound healing, healthy joints and nerve development. With age, these agents seem to decline. “There is evidence that maintaining the proper amount and type of glycosaminoglycans could be protective in aging,” says Johnson. “It hasn’t been an area of focus for aging research, but perhaps there are treatment implications there.”
http://time.com/4083...inked-to-aging/
 


http://www.nature.co...ncomms9570.html

[LeeYa]

A remarkable study!

 

Transcriptome changes as presented here, destabilize the whole system. ( see also: http://www.nature.co...icles/srep13589).

Aging is primarily an epigenetic-driven phenomenon.

 

However - Am I the only one who sees the obvious chance of bypassing the aging process by correcting the expression levels of this few genes?

 

Edited by LeeYa, 27 October 2015 - 12:29 AM.

[sthira]

A remarkable study!

Transcriptome changes as presented here, destabilize the whole system. ( see also: http://www.nature.co...icles/srep13589).
Aging is primarily an epigenetic-driven phenomenon.

However - Am I the only one who sees the obvious chance of bypassing the aging process by correcting the expression levels of this few genes?

How?

[Logic]

 

A remarkable study!

Transcriptome changes as presented here, destabilize the whole system. ( see also: http://www.nature.co...icles/srep13589).
Aging is primarily an epigenetic-driven phenomenon.

However - Am I the only one who sees the obvious chance of bypassing the aging process by correcting the expression levels of this few genes?

How?

 

 

+1 on the how!??  

 

I was thinking of taking the shotgun approach to studying this by looking for substances that upregulate all the downregulated genes and vica versa, but that would take a looong time!

A better approach would be to find key genes in which a change would affect all the others and look at ways of upregulating those.

[sthira]

A remarkable study!

Transcriptome changes as presented here, destabilize the whole system. ( see also: http://www.nature.co...icles/srep13589).
Aging is primarily an epigenetic-driven phenomenon.

However - Am I the only one who sees the obvious chance of bypassing the aging process by correcting the expression levels of this few genes?

How?

+1 on the how!??

I was thinking of taking the shotgun approach to studying this by looking for substances that upregulate all the downregulated genes and vica versa, but that would take a looong time!
A better approach would be to find key genes in which a change would affect all the others and look at ways of upregulating those.

Or edit defective genes and epigenome through progress in CRISPR/CAS9? But are we still begging the how? We may have glimpses of this powerful anti-aging, anti-disease tool -- crispr craze -- now where to aim it at the millions of defects?

Edited by sthira, 27 October 2015 - 08:00 AM.

[LeeYa]

 

 

 

However - Am I the only one who sees the obvious chance of bypassing the aging process by correcting the expression levels of this few genes?

How?

+1 on the how!??

I was thinking of taking the shotgun approach to studying this by looking for substances that upregulate all the downregulated genes and vica versa, but that would take a looong time!
A better approach would be to find key genes in which a change would affect all the others and look at ways of upregulating those.

Or edit defective genes and epigenome through progress in CRISPR/CAS9? But are we still begging the how? We may have glimpses of this powerful anti-aging, anti-disease tool -- crispr craze -- now where to aim it at the millions of defects?

 

 

 

An engineering approach:

 

1) Gene therapy for the 3 downregulated clusters, i.e. with AAV vectors

2) CRISPRi for the 4 upregulated clusters (http://www.cell.com/...8674(13)00211-0)

 

- Yes, I think there are indeed a few key genes in which a change would affect all the others, but the shotgun approach should work as well.

 

- Millions of defects? Even if you assume that some tissue specific gene expression changes are not detected by this blood examination, roughly an estimated number of 2'000 age-dependent genes have to be covered.

 

- Editing the epigenome back to youth would be even better, but there is still a long way until you can do this in every cell in vivo. However, gene therapy is technically available today, and can bypass epigenetic repression. Its immediate application is"only" hindered by ethical issues, by FDA and by high costs.

Edited by LeeYa, 27 October 2015 - 11:33 PM.

[niner]

Regarding the question of "How?",  they could dose people with various compounds and check the behavior of each by looking at the effect the treatment has on expression levels.  The goal would be to find compounds that broadly modulate expression in a youthful direction.  This has been done in the past for at least some compounds.  I recall someone looked at resveratrol this way.  It moved a lot of genes, but I don't know how that would compare to this list.  It would be interesting to look at that.  You could also look at other interventions this way, like diet and exercise.  I suspect exercise or CR would make your expression profile look younger.

[John Schloendorn]

A problem with using chronological age as the independent variable is that it doesn't correlate particularly well with aging-related dysfunction, disease and death.  This puts a limit on the quality of "aging genes" that can be discovered -- they can't ever get any more predictive than a calendar, and that's not very good.  

 

By extension, any drug targets that can be discovered in this way will inherit the same quality limit.  If we're looking for a drug to take a 50 year old's chance of dying and set it back to a 45 year old's, then the natural probability of the 45 year old to die first, will blur our ability to see the correct targets in complex data sets.  Given how rare such drug targets will be (if they exist at all), and how enormous the data sets are, I doubt that we can live with the current numbers (but that's just a gut guess -- any mathematical treatment of this issue would be welcome :-). 

 

You could use time-to-death as the independent variable instead.  We certainly care about it a lot more than calendar age.  But it's not really practical to do it in humans, because we age so slowly.  One could blindly trust data from short-lived animals on this (does mouse gene expression predict human time to death better than human calendar age?), or perhaps get a hold of a tissue bank with frozen human samples with known time to death from the past (does it exist?). 

 

Does anybody have any other suggestions? 

 

 

 

[sthira]

Does anybody have any other suggestions?

What is your opinion about what Liz Parrish is evidently doing?

[treonsverdery]

well,

a person once tied me to chair then told me things about the future,  that person said a C. (E) Parrish actually got physiological cancer unexpectedly, thus if she has not noticed yet, I suggest lots of antioxidants as well as possibly some kind of genetic screening.  Peace is possible

 

Edited by treonsverdery, 03 November 2015 - 07:36 PM.

[treonsverdery]

well,

a person once tied me to chair then told me things about the future,  that person said a C. (E) Parrish actually got physiological cancer unexpectedly, thus if she has not noticed yet, I suggest lots of antioxidants as well as possibly some kind of genetic screening.  Peace is possible

also metformin along with longevizing reduces risk of carcinogenesis

[LeeYa]

A problem with using chronological age as the independent variable is that it doesn't correlate particularly well with aging-related dysfunction, disease and death.  This puts a limit on the quality of "aging genes" that can be discovered -- they can't ever get any more predictive than a calendar, and that's not very good.  

 

By extension, any drug targets that can be discovered in this way will inherit the same quality limit.  If we're looking for a drug to take a 50 year old's chance of dying and set it back to a 45 year old's, then the natural probability of the 45 year old to die first, will blur our ability to see the correct targets in complex data sets.  Given how rare such drug targets will be (if they exist at all), and how enormous the data sets are, I doubt that we can live with the current numbers (but that's just a gut guess -- any mathematical treatment of this issue would be welcome :-). 

 

You could use time-to-death as the independent variable instead.  We certainly care about it a lot more than calendar age.  But it's not really practical to do it in humans, because we age so slowly.  One could blindly trust data from short-lived animals on this (does mouse gene expression predict human time to death better than human calendar age?), or perhaps get a hold of a tissue bank with frozen human samples with known time to death from the past (does it exist?). 

 

Does anybody have any other suggestions? 

 

You are right.

 

A better strategy would be the measurement of Age-dependent CpG-Sites. (PMID: 24490752)

 

 

 

 

 

 

[niner]

A problem with using chronological age as the independent variable is that it doesn't correlate particularly well with aging-related dysfunction, disease and death.  This puts a limit on the quality of "aging genes" that can be discovered -- they can't ever get any more predictive than a calendar, and that's not very good.  

 

By extension, any drug targets that can be discovered in this way will inherit the same quality limit.  If we're looking for a drug to take a 50 year old's chance of dying and set it back to a 45 year old's, then the natural probability of the 45 year old to die first, will blur our ability to see the correct targets in complex data sets.  Given how rare such drug targets will be (if they exist at all), and how enormous the data sets are, I doubt that we can live with the current numbers (but that's just a gut guess -- any mathematical treatment of this issue would be welcome :-). 

 

You could use time-to-death as the independent variable instead.  We certainly care about it a lot more than calendar age.  But it's not really practical to do it in humans, because we age so slowly.  One could blindly trust data from short-lived animals on this (does mouse gene expression predict human time to death better than human calendar age?), or perhaps get a hold of a tissue bank with frozen human samples with known time to death from the past (does it exist?). 

 

Does anybody have any other suggestions? 

 

I don't think that's the kind of predictiveness that they're talking about.  The expression levels of these genes are not linear functions of age; many are more binary (or more likely sigmoidal); they are turned off or on somewhere in the course of life.  No one would look for a compound to set a 50 year-old's chance of dying to that of a 45 year-old's; not only is there little point in that, but we couldn't do it if we wanted to on the basis of this data and present technology.  Instead, we would look for compounds that make us "more youthful".   Knowing which directions in expression level correspond to "more youthful" is a good way to start such a search.

[Danail Bulgaria]

... No one would look for a compound to set a 50 year-old's chance of dying to that of a 45 year-old's; ... 

 

 

Depends how many times you can apply the chances reversal. You may do it 50 to 45 once, then 45 to 40 later, and so on, and so on, until you reach the chances of death of a 20 years old young and strong man. And that definately worths it. 

 

Or how many time you can be in yours 45. For example you go from 50 to 45 once, then after five years again to 45, and five years later again. This also worths it. At 45 people are still cappable of enjoying the life. 

[Logic]

A good starting point?

 

Systemic attenuation of the TGF-β pathway by a single drug simultaneously rejuvenates hippocampal neurogenesis and myogenesis in the same old mammal

...Various studies have demonstrated that not just one signaling pathway, but a network of highly interactive pathways including Notch, Wnt, BMP, Shh, TNF-α, IGF, and IL-6 are affected by the aging process...

http://www.ncbi.nlm....les/PMC4494916/

 

More here:

http://www.longecity...-ageing-brains/

http://www.longecity...f-irina-conboy/

 

Pentoxiflline

Nicotine
Galunisertib CAS# 700874-72-2
TEW-7197 CAS# 1352608-82-2
Ganoderma Lucidum (Reishi)

"TGF-β1 Type I Receptor Kinase Alk5 inhibitor 2-(3-(6-Methylpyridin-2-yl)-1H-pyrazol-4-yl)-1,5-naphthyridine (Enzo Life Sciences) diluted in sunflower seed oil to a concentration of 57.4 μM."

[Florian Xavier]

In 2010, i posted on the official sens forum that an anti-tgfb1 would be beneficial to aging, and it's not a joke

 

i was in the futur 

Edited by Florian Xavier, 12 November 2015 - 10:50 AM.