Fight Aging!

As I said earlier this week I believe that fixing certain forms of damage/waste would likely yield good results even alone. It would depend of course on what you do.

Senolytics alone would be useful but Senolytics + Stem cells could yield good results and we have good reason for thinking this.

Cleaving glucosepane is another therapy likely to yield good results and I could easily see a combination of that and senolytics being very potent.

The bottom line however is no one knows because no one has tested it. The simple answer of course is now to test it and find out! The MMTP will be doing just that and finding out what the data says.

SYNERGY IS SOMETHING PROVEN, for better and for worse.

LA SINERGIA ES ALGO COMPROBADO, PARA LO BUENO Y PARA LO MALO.

I disagree, I think if you tackle the following 2 major problems
you will definitely extend life by 30 years.

1) Detection and destruction of damaged cells including cancer cells.

2) Harvesting & adding telomere length and cloning healthy stem for specific injection back to the patient.

The main road block after and additional 30 years is the Brain, the brain does not replace it's self the same as other organs it does something quite different.

@Rob Flores: Neither of those will clear transthyretin amyloid or cross-links, either of which seems capable of killing you over the present human lifespan whatever your stem cells are doing.

My moneys on Glucosepane being the big problem considering its effects on stem cells, signalling environment and on telomeres as a downstream result of that plus the inflammation it causes etc...

I think we could get good mileage with cleaving AGE, Stem cells and Senolytics.

Let us hope we can find an AGE cleaver soon.

REASON:

My understanding is the accumulation of debris that accumulate in the body
is usually handled by specialized cells/systems. These cells degrade in
their ability to the task of cleaning up the debris. Why do they degrade?
because of their numbers or because of they have too many errors in their
DNA instruction set. Either way if you replace the root cells that create
them it stands to reason that they would improve a body's ability to clear
the debris that cause some of the effects you mention.

If some of the lethal debris is just a product that is a trade off that
longer lived high metabolism type animals have accept then I do believe you might be correct.

In that case nano-engineered clearance mechanisms
are indicated which means we will see it 30-40 years down the road, if nothing else works.

@Reason @Rob Flores (long message, everyone is warned :) in summary immortality is not something unfeasible (though highly implausible and our chances are of fractions), cancerous cells do it, gonadal stem cells do it, we're next !

''
@Rob Flores: Neither of those will clear transthyretin amyloid or cross-links, either of which seems capable of killing you over the present human lifespan whatever your stem cells are doing.''

''REASON:

My understanding is the accumulation of debris that accumulate in the body
is usually handled by specialized cells/systems. These cells degrade in
their ability to the task of cleaning up the debris...
If some of the lethal debris is just a product that is a trade off that
longer lived high metabolism type animals have accept then I do believe you might be correct.
In that case nano-engineered clearance mechanisms
are indicated which means we will see it 30-40 years down the road, if nothing else works.''

Hi Reason and Rob !

Exactly, pigment age residues (lipofuscin, ceroid, thransthyretin, protein aggregates, tau, beta-amyloid, A2E, etc) removal through a special nanorobots bacterial-junk degrading enzymes filled
targeting the proteasomes, lysosomes, phagosomes and the extra-cellular milieu would circumvent
the accumulation deposition problem and irrerversibility/undegradability problem (such as lipofuscin terminal pigment); for these
residues can only be diluted through cell cycling.
If you read the man's aging research paper in entirety of this news,
he talks that the mother cell when dividing to make daughter cells, they are residue-less but the mother is becoming
bigger and as it replicates, it keeps on making daughter cells, but at a certain point some daughter cells start to
accumulate lipofuscin and other residues too by damage residue 'sharing' transfer from the 'aged' mother to young daughter (the mother is the main 'original' source divider/carrier of damages and junk depots residues), and when she
reaches about 17 microns size - she stops replicating (no more ''brand new'' spanking daughter cells residue-free, cell size = cell's own aging counting mechanism, cells that are enlarged are senescent or apoptosing, in death throes), this correlates
with her entering replicative senescence onset and telomere M1 replicative point at 5kb; and 100% mother lipofuscin accrual; and 17 micron mother cell final 'death' size),

Reason, thransthyretin is diluted in dividing cells (even the man in the research paper says dividing cells accumulate almost no damage whatsoever) not in long-lived non-dividing post-mitotic cells
as such accumulate in humans (especially centenarians who succomb of cardiac transthyretin amyloidosis (also called 'heart browning' (brown transthyretin undegradable pigment accumulation giving heart browning in centenarians) not to be confused with skin browning 'UV tanning' by Maillard reaction glycation/glycoxidation process of AGEs)
We can circumvent that using nanorobots targeting these junk residues such as SENS LysoSENS therapy which I hope to god works (like for real, not therapeutically (slightly reduce lipofuscin total count by degrdation nanorobot removal), but in entire body and Entire Cells to make for rejuvenation) otherwise we are....... Otherwise, I will give it to you
there is no way we can stop this tide of junk in proteasomes and lysosomes, including transthyretin in centenarians causing their death. Only other way
is oxidative stress delaying through the redox, delaying this junk deposition accumulation rate.
It may not lead to immortality but yes that half a millenium (500 years lifespan) could be possible.

In the research paper, Stefan I. Liochev researcher says :

''In this regard, the toxic Fenton reaction proceeds even at normal conditions and the damage caused by it is inevitable.
In fact, one of the main reasons immortality and even dramatic increase of longevity and of health span are impossible is that the very agents, such as sugars, H2O2, iron, oxygen, sunlight, etc., that we need for survival are, on the other hand, even at normal levels, more or less direct causes of aging and thus of our demise''

Than later he continues :

''...I do not share the view that near-immortality is possible, for reasons only inferred above;
in the cause of brevity they cannot be discussed in more detail here.
I also agree with the view [14,17] that the increase of lifespan will eventually slow down and approach a limit (the question is: to what extent could the maximal lifespan be increased by novel approaches?).
In this regard, the view that by prevention and/or repair health and lifespan can be at least moderately extended seems logical to me.''

''...(the question is: to what extent could the maximal lifespan be increased by novel approaches?). ''

To answer is question, mostly through redox modulation or aggregates removal can replicative lifespan be extended beyond maximal lifespan.
I feel it's sad that he doesn't believes in immortality or let's say semi-immortality/near-immortality...it may be a stretch I'll give it to him
but it doesn't mean it is Impossible, we will crack that mortality. Call me crazy.

For example, he talks about Fenton reactions by hydroxyl radical and iron, yet he forgets (or possibly simply just did not know...we can't know everything! And aging is so complex it's redundant and we forget things)
the major contributor of iron to catalyze Fenton reaction is in the residues themselves (lipofuscin is iron-rich matter) and the dead mitochondria effetes that produce H2O2 and through iron make for hydroxyl radical formation
all happening in the proteasome and lysosomes junk depots). If we are capable of removing these resides we cut that Fenton reaction from happening, as he says iron chelation helps a lot it removes iron from lipofuscin or quenches hydroxyls (the largest iron containing residue),
he mentions resveratrol as iron chelator and hydroxyl radical quencher/scavenger...this is in domain of anti-oxidants such a grapes full of senolytics such as resveratrol and quercetin (which are senolytics and iron chelators) but
they do not make for immortality either...senolytics, iron chelators and hydroxyl scavengers are helpful health-wise (just like quercetin and dasatinib) but will not make humans
go much above MLSP (people eating fruits full of them never got pass 120).
This means it is not major contributor...what is the major contributor and I'm going to answer his own paper
is the redox (assurance systems that he calls) and the residue removal (by damage accumulation).

@Rob

Telomerase therapy has been tried and elongating telomeres is a very good option,
is just isn't easy to do, or yielding miraculous results (that is because oxidative stress is ongoing process and replicative end-problem too) and telomerases acts on short telomeres rather that long ones
plus it is evacuated from the nucleus during oxidative stress during aging (telomerase reduces ROS production only in low oxidative stress state);
so that's a
double whammy, let us see what happens with Mrs. Parrish results...we'll see then
if her telomeres were lenghten that much (most likely only her short telomeres) and if she has some cancerous marker through the roof
I say it will increase by 15-30 years max, same thing for stem cell + senolytic + telomerase + CR + antioxidants and other therapy, 30 years max average lifespan improvement in humans (a big if, 50 years increase would be magical).

Why does yeast age?

There are no extra-cellular crosslinks, no senescent cells, no extra-cellular aggregates, no non replacement of stem cells, no cancer. Out of the SENS categories of damage only intra-cellular aggregates and mitochondrial mutations are left.

Does this mean if you expressed the mitochondrial genes in the nucleus and periodically administered enzymes capable of breaking down lysosomal aggregates you would get yeast cells with indefinite lifespan?

To add to my above comment, it seems like a good way to sort out whether or not nuclear DNA damage beyond that causing cancer is a driver of aging. If you obviated mitochondrial DNA damage by sticking the mitochondrial genes in the yeast nucleus and then got rid of the intra-cellular aggregates, then surely if the yeast still aged DNA damage would be important?

My opinion on what if was fixed would have the biggest effect is age related epigenetic changes. Of course damage and the epigenome are interlinked. Damage causes epigenetic changes as well as natural epigenetic changes cause damage.

The effect of epigenetic reprogramming is pretty astonishing. For example if you take a neuron from an old person and a neuron from a young person and reset its epigenetic program they are indistinguishable from each other. Another example is the recent study on Caenorhabditis elegans which paused epigenetic drift for 30-40% of their lifespan and their mortality rate was shifted parallel by 30-40%.

There are of course additional examples of how epigenetic reprogramming causes dramatic rejuvenation at the cellular level. As well as many less than halfway measures, such as rejuvenating some aspect of the cell environment controlled by the epigenome causing partial rejuvenation in the body.

@Jim

Hi Jim,

Exactly. Removing/degrading lysosomal aggregates allows immortality and indefinite replicative lifespan. Mitochondrial gene nucleus transfer is also very helpful, but if the junk stays it won't make any difference. This residues junk Is the major source of Fenton ROS reactions, so basal 'background junk ROS', when the total junk count rises so does the cumulative total ROS. It's a vicious circle of ROS production by increasing total ROS producing-junk being deposed in proteasomal, lysosomal and autophagic system.
Also, nuclear damage contributes to aging because the nucleus houses the chromosomes full of DNA double strands and the chromosomes' end telomeres that contain the telomeric DNA repeats, which are Causal to replicative lifespan/senescence (by telomeric DNA base pair loss done by replicative end-problem creating telomeric DNA damage such as telomeres y-H2AX foci formation).

@Santi

Hi Santi, that is another option that I so hope could solve this whole aging problem. I used to be 100% in (epi)genetic reprogrammation camp (now I'm half-half, damage and reprogrammation), and Extremely believe it could be the final saving grace and big 'shocker' that would allow immortality as very real possibility. Why try to continue to fight off aging, damages, aggregates, junk, etc (it's like an unsurmountable mountain where we play catch-up patch-up to evade our own death - for a little longer) when we can CODE DE RE code the DNA/RNA code ourselves by reprogramming the whole thing back to original young code state. iPSCs stem cell reprogrammation is a good start. And, as you say, neuron epigenetic reprogramming is great, even more than great because unlike iPSCs (diving/cycling/replicates) neuron are part of the body's non-dividing/non-cycling/non-replicating long-lived post-mitotic cells that you can have since your very birth. They are critical only ones accumulating lysosomal age pigments and major contributors to the intrinsic aging progression. The fact we can reprogramm long-lived post-mitotic cells means we could supplant damage, residues, junk, and thus, allow immortality.

@ Jim
This is very interesting! Should then SENS or other scientists work out a simpler model of the non-aging yeast first before embarking on very difficult journey of creating a non-aging mouse (per SRF)?

When I try to look briefly on the web at the state of anti-aging science on yeast, science news on Sir2 few years old come up typically. What is the current state of the art then anybody? Surly such a proof on immortal yeast would help with SRF efforts.

Maybe we can use lastest efforts on cas9CRISPR to fix any changes to the nuclear and mitochondiral DNA. Find a way to fix the epigenomes of the nuclear DNA. And maybe any experimental enzymes could clean up lysosomes - without a fear of killing the organism during the phase III trials ;-)

BTW, why SENS "seven sins" do not worry about changes to the cell filaments or microtubules. There surely have to be more damage and dysregulations of them in the cell structure/state.

Actually a single celled organism like yeast probably won't be a good model for human aging as yeast cells don't have to worry about cancer. Also when genomic stress is detected in a multi cellular organism like a mouse or human cellular apotosis or senescence are options, but these don't exist for yeast (that would be suicide).

I believe the SENS Research foundation's position was that perhaps in long lived animals like humans cells have such high DNA fidelity due to the risk of cancer that general non cancerous DNA mutations may not be important in aging.

Blasco has published a new paper about telomeres and aging, submitted for your interest:

http://f1000research.com/articles/5-89/v1