The Age-Reversed Animal

Outcome

An animal model that can experience normal biological aging which will then be reversed. The cycle of aging-youth-aging will be repeated at least once.

Why the Need?

There is a need to demonstrate the new capabilities and opportunities that the field of longevity and age reversal opens for humankind. An animal whose aging can be effectively reversed will provide a powerful demonstration of the promise of age reversal for human beings, and will demonstrate a better and more holistic understanding of the aging process.

Stipulations for a Successful Breakthrough Solution

    The age-reversed animal should be as advanced as possible – up to the primate level The longer the animal lives (i.e. the more youth-age-youth cycles it undergoes), the better
  • The animals must be experimented upon in an ethical and humane fashion as much as possible.

Promising Technologies for Solutions

There are many technologies and drug candidates that have the potential to achieve at least parts of this breakthrough. It also seems likely that genetic engineering will need to be used in order to produce the first ‘ever-living mouse’.

Expected year for proof of concept: 2025
Expected year for mass-scaling: 2030

Does the animal have to retain its “consciousness” through the cycles?
For example, if it learns its way through a maze during a long life, then it is made young again, then ages again, does it have to remember its way through the maze? If not, growing new organs in situ could be a solution. If retaining memory is required (obviously more desirable for humans), growing a new replacement brain may not be an option because the memories cannot be transferred.

Nice point @Lodder545! I personally think retaining the same consciousness is critical, so perhaps replacement of organs other than the brain :slight_smile:

This has already been achieved

I think the work that is ongoing related to the introduction of ipsc transcription factors to live animals has already yielded results in this area…

Do personal and societal implications enter the conversation?

@Oakshade, could you tell us more?

@nlc, absolutely!

Oakshade is correct. Age-reversal of human cells was first accomplished in 1998 (Bodnar et al. https://doi.org/10.1126/science.279.5349.349) and in human tissue in 2000 (Funk et al. https://doi.org/10.1006/excr.2000.4945).

To an extent, this was also accomplished in animals in 2010 by DePinho’s group at Harvard (https://doi.org/10.1038/nature09603) and in 2012 by Blasco’s group at CNIO ( https://doi.org/10.1002/emmm.201200245).

For an in-depth academic discussion, see my textbook “Cells, Aging, and Human Disease” (Oxford University Press, NY, 2004). For references to the later works, see my January OB Geriatrics article: https://doi.org/10.21926/obm.geriatr.1901031.

Aging has already been reversed in human cells and in human tissues. The issue is to what extent we can do so in vivo, including not only animals, but human beings. We are quite capable of this technically, but until now the primary obstacle has been a conceptual one which prevented us from fully understanding the complexity involved in the fundamental aging process. Aging is far more than mere entropy.

Responding to Nick: a societal implication to consider: Parts of the world already experience food shortages, if age reversal becomes a reality, what are the implications for feeding the world’s hungry? Will such a process be available to everyone or only the world’s elites? To criminals? To the mentally ill?

@Elena_Milova, @SvenB, @adampowell, you might have thoughts on that.

Also see:

  • [Population aging and age-related causes of death](https://community.xprize.org/longevity/discussion/209/population-aging-and-age-related-causes-of-death)
  • [Population increase and higher medical costs](https://community.xprize.org/longevity/discussion/126/population-increase-and-higher-medical-costs)

A couple of comments:

First, I understand the need for using a primate as an experimental animal model. However, restoring ‘youthfulness’ to an aged primate, then returning the primate to an aged state (and there is the possibility of accelerated aging) is not ‘humane’ and would be considered cruel in any court of law – and there WILL be lawsuits, as there are already lawsuits by animal rights groups to stop bio-medical chimpanzee experiments (involving ‘personhood’ of said primates, but this distinction is not necessary to prove 'animal cruelty).

Secondly, use of iPSCs to stop or slow aging (the latter being more likely) was all the rage back in 2012/13…but since then, while research has continued…breakthroughs – on the systemic level – have been slow in coming. Cell re-programming took a hit with the Riken Institute scandal (falsified results from a ‘simplified’ cell reprogramming process, dubbed STAP), but work continues, albeit more cautiously. There is some promising work out there regarding arresting stem cell differentiation (involving intervention of TF complex activity and cis-regulatory elements, and even some epigenetic alterations) and even ‘reversing’ cell fate. Challenges exist in fully controlling cell fate and stopping unchecked proliferation (which can produce unwanted immune responses and neoplasia/cancer).

Also, there are the ‘parabiosis’ (rat) experiments from a few years ago in which the circulatory system of a healthy young rat was coupled to that of an older rat; after a period of time, the older rat appeared to have restored muscle tone and memory performance ability. This experiment became sensationalized, and also became the inspiration for the ‘Silicon Valley’ episode ‘Blood Boy’ (with one perversely hilarious scene). The problem is that these experiments did not demonstrate the specific cause of the ‘restored’ youthful vigor and cognition in the aged rat. Meanwhile, the few reproducibility experiments have not been conclusive. However, Snyder et al recently (2019) showed that resident memory T cells localized to and remained in targeted lung tissue for longer periods after parabiosis and that this was associated with “better clinical outcomes”

That said, I do believe that blood circulation – specifically, maintaining micro-circulation* in the brain – is key to preventing the cognitive deficits and decline associated with aging (including preventing common forms of dementia). So, perhaps developing a micro-circulation animal model (or an advanced organoid, as a animal model surrogate) would be highly beneficial in Aging research.

*Recent work by Cruz-Hernandez et al has found that immune (‘sentinel’) cells known as neutrophils pile up in the micro vasculature (capillaries), causing blockages and atrophy (due to oxygen and nutrient deprivation) of both capillaries and tissue.

Thank you for the comments, @marz62! This is very helpful.

CC @JessicaYoon & @SamBlake

@Fossel - I find the research you cite quite fascinating…but, I always wonder about the phrase ‘aging reversal’ (and similar phrases)…

What exactly characterizes these cells or cell cultures (ex vivo or* in vitro*) to make them ‘age-reversed’? Did they “live longer” (meaning more cell divisions [daughter cells] before senescence/loss of biological function or cell death?) Did they stop dividing but maintain healthy functioning longer (this is important to know as continuous cell division is essentially equivalent to cancer).

[note: Funk et al expressed a telomerase subunit to restore the healthy cell phenotype – but a healthy cell, as it divides, shortens its telomeres, via the action of telomerase; not doing so is a hallmark of cancer progression]). The loss of expression of this catalytic subunit is “normal”. So, does this re-expression (the return to a healthy phenotype [assessed by mRNA assays] come at a cost (to the cell)?

When we say ‘age reversal’ we generally mean returning the cell to an undifferentiated (stem-like) state – *toti *or pluri potency – but do we assume that accumulated DNA damage just “goes away”…?

Following this, it would seem that the chronological age of the person (e.g., a future human undergoing complete ‘cell reprogramming’ as a ‘youth restoration therapy’) may likely be important, as the older we get, the more DNA damage accumulates ( see: Thomasetti & Vogelstein 2016/17).

I find cell reprogramming both fascinating and problematic. Thoughts?