LongeCity has been doing advocacy and research for indefinite life extension since 2002. With the Methuselah Foundation and the M-Prize’s rise in prominence and public popularity over the past few years, it is sometimes easy to forget the smaller-scale research initiatives implemented by other organizations.
LongeCity seeks to conquer the involuntary blight of death through advocacy and research. They award small grants to promising small-scale research initiatives focused on longevity. The time to be doing this is now, with the increasing popularity and public awareness of Citizen Science growing. The 2020 H+ Conference’s theme was The Rise of the Citizen Scientist. Open –Source and Bottom-Up organization have been hallmarks of the H+ and TechProg communities for a while now, and the rise of citizen science parallels this trend.
Anyone can have a great idea, and there are many low-hanging fruits that can provide immense value and reward to the field of life extension without necessitating large-scale research initiatives, expensive and highly-trained staff or costly laboratory equipment. These low-hanging fruit can provide just as much benefit as large scale ones – and, indeed, even have the potential to provide more benefit per unit of funding than large-scale ones. They don’t call them low-hanging fruit for nothing – they are, after all, potentially quite fruitful.
In the past LongeCity has raised funding by matching donations made by the community to fund a research project that used lasers to ablate (i.e. remove) cellular lipofuscin. LongeCity raised $8,000 dollars by the community which was then matched by up to $16,000 by SENS Founation. A video describing the process can be found here. In the end they raised over $18,000 towards this research! Recall that one of Aubrey’s strategies of SENS is to remove cellular lipofuscin via genetically engineered bacteria. Another small-scale research project funded by LongeCity involved mitochondrial uncoupling in nematodes. To see more about this research success, see here.
LongeCity’s 3rd success was their project on Microglia Stem Cells in 2010. The full proposal can be found here, and more information on this second successful LongeCity research initiative can be found here.
These are real projects with real benefits that LongeCity is funding. Even if you’re not a research scientist, you can have an impact on the righteous plight to end the involuntary blight of death, by applying for a small-scale research grant from LongeCity. What have you got to lose? Really? Because it seems to me that you have just about everything to gain.
LongeCity has also contributed toward larger scale research and development initiatives in the past as well. They have sponsored projects by Alcor, SENS Foundation and Methuselah Foundation. They crowdsourced a longevity-targeted multivitamin supplement called VIMMORTAL based on bottom-up-style community suggestion and deliberation (one of the main benefits of crowdsourcing).
So? Are you interested in impacting the movement toward indefinite life extension? Then please take a look at the various types of projects listed below that LongeCity might be interested in funding.
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The following types of projects can be supported:
• Science support: contribution to a scientific experiment that can be carried out in a short period of time with limited resources. The experiment should be distinguishable from the research that is already funded by other sources. This could be a side-experiment in an existing programme, a pilot experiment to establish feasibility, or resources for an undergrad or high-school student.
• Chapters support: organizing a local meeting with other LongeCity members or potential members. LongeCity could contribute to the room hire, the expenses of inviting a guest speaker or even the bar tab.
• Travel support: attendance at conferences, science fairs etc. where you are presenting on a topic relevant to LongeCity. Generally this will involve some promotion of the mission and/or a report on the then conference to be shared with our Members
• Grant writing:
Bring together a team of scientists and help them write a successful grant application to a public or private funding body. Depending on the project, the award will be a success premium or sometimes can cover the costs of grant preparation itself.
• Micro matching fundraiser:
If you manage to raise funds on a mission-relevant topic, LongeCity will match the funds raised. (In order to initiate one of these initiatives LongeCity usually also requires that the fundraiser spends at least 500 ‘ThankYou points’ but this requirement can be waived in specific circumstances.)
• Outreach:
Support for a specific initiative raising public awareness of the mission or of a topic relevant to our mission. This could be a local event, a specific, organized direct marketing initiative or a media feature.
• Articles:
Write a featured article for the LongeCity website on a topic of interest to our members or visitors. LongeCity is mainly looking for articles on scientific topics, but well-researched contributions on a relevant topic in policy, law, or philosophy are also welcome.
Grant Size:
‘micro grants’ — up to $180
‘small grants’ — up to $500
Grant applications exceeding $500 can be received, but will not be evaluated conclusively under the small grants scheme. Instead, LongeCity will review the application as draft and may invite a full application afterward.
Decisions as part of the small grants programme are usually pretty quick and straightforward. However please contact LongeCity with a proposal ahead of time, as they will not normally consider applications where the money has already been spent!
Proposals can be as short or elaborate as necessary, but normally should be about half a page long.
Only LongeCity Members can apply, but any Member is free to apply on behalf of someone else — thus, non-Members are welcome to find a Member to ‘sponsor’ their application.
You can also use the ideas forum to prepare the proposal. For general questions, or to discuss the proposal informally, feel free to contact LongeCity at the above email.
In this essay I argue that technologies and techniques used and developed in the fields of Synthetic Ion Channels and Ion Channel Reconstitution, which have emerged from the fields of supramolecular chemistry and bio-organic chemistry throughout the past 4 decades, can be applied towards the purpose of gradual cellular (and particularly neuronal) replacement to create a new interdisciplinary field that applies such techniques and technologies towards the goal of the indefinite functional restoration of cellular mechanisms and systems, as opposed to their current proposed use of aiding in the elucidation of cellular mechanisms and their underlying principles, and as biosensors.
In earlier essays (see here and here) I identified approaches to the synthesis of non-biological functional equivalents of neuronal components (i.e. ion-channels ion-pumps and membrane sections) and their sectional integration with the existing biological neuron — a sort of “physical” emulation if you will. It has only recently come to my attention that there is an existing field emerging from supramolecular and bio-organic chemistry centered around the design, synthesis, and incorporation/integration of both synthetic/artificial ion channels and artificial bilipid membranes (i.e. lipid bilayer). The potential uses for such channels commonly listed in the literature have nothing to do with life-extension however, and the field is to my knowledge yet to envision the use of replacing our existing neuronal components as they degrade (or before they are able to), rather seeing such uses as aiding in the elucidation of cellular operations and mechanisms and as biosensors. I argue here that the very technologies and techniques that constitute the field (Synthetic Ion-Channels & Ion-Channel/Membrane Reconstitution) can be used towards the purpose of the indefinite-longevity and life-extension through the iterative replacement of cellular constituents (particularly the components comprising our neurons – ion-channels, ion-pumps, sections of bi-lipid membrane, etc.) so as to negate the molecular degradation they would have otherwise eventually undergone.
While I envisioned an electro-mechanical-systems approach in my earlier essays, the field of Synthetic Ion-Channels from the start in the early 70’s applied a molecular approach to the problem of designing molecular systems that produce certain functions according to their chemical composition or structure. Note that this approach corresponds to (or can be categorized under) the passive-physicalist sub-approach of the physicalist-functionalist approach (the broad approach overlying all varieties of physically-embodied, “prosthetic” neuronal functional replication) identified in an earlier essay.
The field of synthetic ion channels is also referred to as ion-channel reconstitution, which designates “the solubilization of the membrane, the isolation of the channel protein from the other membrane constituents and the reintroduction of that protein into some form of artificial membrane system that facilitates the measurement of channel function,” and more broadly denotes “the [general] study of ion channel function and can be used to describe the incorporation of intact membrane vesicles, including the protein of interest, into artificial membrane systems that allow the properties of the channel to be investigated” [1]. The field has been active since the 1970s, with experimental successes in the incorporation of functioning synthetic ion channels into biological bilipid membranes and artificial membranes dissimilar in molecular composition and structure to biological analogues underlying supramolecular interactions, ion selectivity and permeability throughout the 1980’s, 1990’s and 2000’s. The relevant literature suggests that their proposed use has thus far been limited to the elucidation of ion-channel function and operation, the investigation of their functional and biophysical properties, and in lesser degree for the purpose of “in-vitro sensing devices to detect the presence of physiologically-active substances including antiseptics, antibiotics, neurotransmitters, and others” through the “… transduction of bioelectrical and biochemical events into measurable electrical signals” [2].
Thus my proposal of gradually integrating artificial ion-channels and/or artificial membrane sections for the purpse of indefinite longevity (that is, their use in replacing existing biological neurons towards the aim of gradual substrate replacement, or indeed even in the alternative use of constructing artificial neurons to, rather than replace existing biological neurons, become integrated with existing biological neural networks towards the aim of intelligence amplification and augmentation while assuming functional and experiential continuity with our existing biological nervous system) appears to be novel, while the notion of artificial ion-channels and neuronal membrane systems ion general had already been conceived (and successfully created/experimentally-verified, though presumably not integrated in-vivo).
The field of Functionally-Restorative Medicine (and the orphan sub-field of whole-brain-gradual-substrate-replacement, or “physically-embodied” brain-emulation if you like) can take advantage of the decades of experimental progress in this field, incorporating both the technological and methodological infrastructures used in and underlying the field of Ion-Channel Reconstitution and Synthetic/Artificial Ion Channels & Membrane-Systems (and the technologies and methodologies underlying their corresponding experimental-verification and incorporation techniques) for the purpose of indefinite functional restoration via the gradual and iterative replacement of neuronal components (including sections of bilipid membrane, ion channels and ion pumps) by MEMS (micro-electrocal-mechanical-systems) or more likely NEMS (nano-electro-mechanical systems).
The technological and methodological infrastructure underlying this field can be utilized for both the creation of artificial neurons and for the artificial synthesis of normative biological neurons. Much work in the field required artificially synthesizing cellular components (e.g. bilipid membranes) with structural and functional properties as similar to normative biological cells as possible, so that the alternative designs (i.e. dissimilar to the normal structural and functional modalities of biological cells or cellular components) and how they affect and elucidate cellular properties, could be effectively tested. The iterative replacement of either single neurons, or the sectional replacement of neurons with synthesized cellular components (including sections of the bi-lipid membrane, voltage-dependent ion-channels, ligand-dependent ion channels, ion pumps, etc.) is made possible by the large body of work already done in the field. Consequently the technological, methodological and experimental infrastructures developed for the fields of Synthetic
Ion-Channels and Ion-Channel/Artificial-Membrane-Reconstitution can be utilized for the purpose of a.) iterative replacement and cellular upkeep via biological analogues (or not differing significantly in structure or functional & operational modality to their normal biological counterparts) and/or b.) iterative replacement with non-biological analogues of alternate structural and/or functional modalities.
Rather than sensing when a given component degrades and then replacing it with an artificially-synthesized biological or non-biological analogue, it appears to be much more efficient to determine the projected time it takes for a given component to degrade or otherwise lose functionality, and simply automate the iterative replacement in this fashion, without providing in-vivo systems for detecting molecular or structural degradation. This would allow us to achieve both experimental and pragmatic success in such cellular-prosthesis sooner, because it doesn’t rely on the complex technological and methodological infrastructure underlying in-vivo sensing, especially on the scale of single neuron components like ion-channels, and without causing operational or functional distortion to the components being sensed.
A survey of progress in the field [3] lists several broad design motifs. I will first list the deign motifs falling within the scope of the survey, and the examples it provides. Selections from both papers are meant to show the depth and breadth of the field, rather than to elucidate the specific chemical or kinetic operations under the purview of each design-variety.
For a much more comprehensive, interactive bibliography of papers falling within the field of Synthetic Ion-Channels or constituting the historical foundations of the field, see Jon Chui’s online biography here, which charts the developments in this field up until 2011.
First Survey
Unimolecular ion channels:
Examples include a.) synthetic ion channels with oligocrown ionophores, [5] b.) using a-helical peptide scaffolds and rigid push–pull p-octiphenyl scaffolds for the recognition of polarized membranes, [6] and c.) modified varieties of the b-helical scaffold of gramicidin A [7]
Barrel-stave supramolecules:
Examples of this general class falling include avoltage-gated synthetic ion channels formed by macrocyclic bolaamphiphiles and rigidrod p-octiphenyl polyols [8].
Macrocyclic, branched and linear non-peptide bolaamphiphiles as staves:
Examples of this sub-class include synthetic ion channels formed by a.) macrocyclic, branched and linear bolaamphiphiles and dimeric steroids, [9] and by b.) non-peptide macrocycles, acyclic analogs and peptide macrocycles [respectively] containing abiotic amino acids [10].
Dimeric steroid staves:
Examples of this sub-class include channels using polydroxylated norcholentriol dimer [11].
pOligophenyls as staves in rigid rod b barrels:
Examples of this sub-class include “cylindrical self-assembly of rigid-rod b-barrel pores preorganized by the nonplanarity of p-octiphenyl staves in octapeptide-p-octiphenyl monomers” [12].
Synthetic Polymers:
Examples of this sub-class include synthetic ion channels and pores comprised of a.) polyalanine, b.) polyisocyanates, c.) polyacrylates, [13] formed by i.) ionophoric, ii.) ‘smart’ and iii.) cationic polymers [14]; d.) surface-attached poly(vinyl-n-alkylpyridinium) [15]; e.) cationic oligo-polymers [16] and f.) poly(m-phenylene ethylenes) [17].
Helical b-peptides (used as staves in barrel-stave method):
Examples of this class include: a.) cationic b-peptides with antibiotic activity, presumably acting as amphiphilic helices that form micellar pores in anionic bilayer membranes [18].
Monomeric steroids:
Examples of this sub-class falling include synthetic carriers, channels and pores formed by monomeric steroids [19], synthetic cationic steroid antibiotics [that] may act by forming micellar pores in anionic membranes [20], neutral steroids as anion carriers [21] and supramolecular ion channels [22].
Complex minimalist systems:
Examples of this sub-class falling within the scope of this survey include ‘minimalist’ amphiphiles as synthetic ion channels and pores [23], membrane-active ‘smart’ double-chain amphiphiles, expected to form ‘micellar pores’ or self-assemble into ion channels in response to acid or light [24], and double-chain amphiphiles that may form ‘micellar pores’ at the boundary between photopolymerized and host bilayer domains and representative peptide conjugates that may self assemble into supramolecular pores or exhibit antibiotic activity [25].
Non-peptide macrocycles as hoops:
Examples of this sub-class falling within the scope of this survey include synthetic ion channels formed by non-peptide macrocycles acyclic analogs [26] and peptide macrocycles containing abiotic amino acids [27].
Peptide macrocycles as hoops and staves:
Examples of this sub-class include a.) synthetic ion channels formed by self-assembly of macrocyclic peptides into genuine barrel-hoop motifs that mimic the b-helix of gramicidin A with cyclic b-sheets. The macrocycles are designed to bind on top of channels and cationic antibiotics (and several analogs) are proposed to form micellar pores in anionic membranes [28]; b.) synthetic carriers, antibiotics (and analogs) and pores (and analogs) formed by macrocyclic peptides with non-natural subunits. [Certain] macrocycles may act as b-sheets, possibly as staves of b-barrel-like pores [29]; c.) bioengineered pores as sensors. Covalent capturing and fragmentations [have been] observed on the single-molecule level within engineered a-hemolysin pore containing an internal reactive thiol [30].
Summary
Thus even without knowledge of supramolecular or organic chemistry, one can see that a variety of alternate approaches to the creation of synthetic ion channels, and several sub-approaches within each larger ‘design motif’ or broad-approach, not only exist but have been experimentally verified, varietized and refined.
Second Survey
The following selections [31] illustrate the chemical, structural and functional varieties of synthetic ions categorized according to whether they are cation-conducting or anion-conducting, respectively. These examples are used to further emphasize the extent of the field, and the number of alternative approaches to synthetic ion-channel design, implementation, integration and experimental-verification already existent. Permission to use all the following selections and figures were obtained from the author of the source.
There are 6 classical design-motifs for synthetic ion-channels, categorized by structure, that are identified within the paper:
“The first non-peptidic artificial ion channel was reported by Kobuke et al. in 1992” [33].
“The channel contained “an amphiphilic ion pair consisting of oligoether-carboxylates and mono- (or di-) octadecylammoniumcations. The carboxylates formed the channel core and the cations formed the hydrophobic outer wall, which was embedded in the bilipid membrane with a channel length of about 24 to 30 Å. The resultant ion channel, formed from molecular self-assembly, is cation selective and voltage-dependent” [34].
“Later, Kokube et al. synthesized another channel comprising of resorcinol based cyclic tetramer as the building block. The resorcin-[4]-arenemonomer consisted of four long alkyl chains which aggregated to forma dimeric supramolecular structure resembling that of Gramicidin A” [35]. “Gokel et al. had studied [a set of] simple yet fully functional ion channels known as “hydraphiles” [39].
“An example (channel 3) is shown in Figure 1.6, consisting of diaza-18-crown-6 crown ether groups and alkyl chain as side arms and spacers. Channel 3 is capable of transporting protons across the bilayer membrane” [40].
“A covalently bonded macrotetracycle4 (Figure 1.8) had shown to be about three times more active than Gokel’s ‘hydraphile’ channel, and its amide-containing analogue also showed enhanced activity” [44].
“Inorganic derivative using crown ethers have also been synthesized. Hall et. al synthesized an ion channel consisting of a ferrocene and 4 diaza-18-crown-6 linked by 2 dodecyl chains (Figure 1.9). The ion channel was redox-active as oxidation of the ferrocene caused the compound to switch to an inactive form” [45]
B STAVES:
“These are more difficult to synthesize [in comparison to unimolecular varieties] because the channel formation usually involves self-assembly via non-covalent interactions” [47].“A cyclic peptide composed of even number of alternating D- and L-amino acids (Figure 1.10) was suggested to form barrel-hoop structure through backbone-backbone hydrogen bonds by De Santis” [49].
“A tubular nanotube synthesized by Ghadiri et al. consisting of cyclic D and L peptide subunits form a flat, ring-shaped conformation that stack through an extensive anti-parallel β-sheet-like hydrogen bonding interaction (Figure 1.11)” [51].
“Experimental results have shown that the channel can transport sodium and potassium ions. The channel can also be constructed by the use of direct covalent bonding between the sheets so as to increase the thermodynamic and kinetic stability” [52].
“By attaching peptides to the octiphenyl scaffold, a β-barrel can be formed via self-assembly through the formation of β-sheet structures between the peptide chains (Figure 1.13)” [53].
“The same scaffold was used by Matile etal. to mimic the structure of macrolide antibiotic amphotericin B. The channel synthesized was shown to transport cations across the membrane” [54].
“Attaching the electron-poor naphthalenediimide (NDIs) to the same octiphenyl scaffold led to the hoop-stave mismatch during self-assembly that results in a twisted and closed channel conformation (Figure 1.14). Adding the compleentary dialkoxynaphthalene (DAN) donor led to the cooperative interactions between NDI and DAN that favors the formation of barrel-stave ion channel.” [57].
MICELLAR
“These aggregate channels are formed by amphotericin involving both sterols and antibiotics arranged in two half-channel sections within the membrane” [58].
“An active form of the compound is the bolaamphiphiles (two-headed amphiphiles). (Figure 1.15) shows an example that forms an active channel structure through dimerization or trimerization within the bilayer membrane. Electrochemical studies had shown that the monomer is inactive and the active form involves dimer or larger aggregates” [60].
ANION CONDUCTING CHANNELS:
“A highly active, anion selective, monomeric cyclodextrin-based ion channel was designed by Madhavan et al (Figure 1.16). Oligoether chains were attached to the primary face of the β-cyclodextrin head group via amide bonds. The hydrophobic oligoether chains were chosen because they are long enough to span the entire lipid bilayer. The channel was able to select “anions over cations” and “discriminate among halide anions in the order I-> Br-> Cl- (following Hofmeister series)” [61].
“The anion selectivity occurred via the ring of ammonium cations being positioned just beside the cyclodextrin head group, which helped to facilitate anion selectivity. Iodide ions were transported the fastest because the activation barrier to enter the hydrophobic channel core is lower for I- compared to either Br- or Cl-“ [62]. “A more specific artificial anion selective ion channel was the chloride selective ion channel synthesized by Gokel. The building block involved a heptapeptide with Proline incorporated (Figure 1.17)” [63].
Cellular Prosthesis: Inklings of a New Interdisciplinary Approach
The paper cites “nanoreactors for catalysis and chemical or biological sensors” and “interdisciplinary uses as nano –filtration membrane, drug or gene delivery vehicles/transporters as well as channel-based antibiotics that may kill bacterial cells preferentially over mammalian cells” as some of the main applications of synthetic ion-channels [65], other than their normative use in elucidating cellular function and operation.
However, I argue that a whole interdisciplinary field and heretofore-unrecognized new approach or sub-field of Functionally-Restorative Medicine is possible through taking the technologies and techniques involved in in constructing, integrating, and experimentally-verifying either a.) non-biological analogues of ion-channels & ion-pumps (thus trans-membrane membrane proteins in general, also sometimes referred to as transport proteins or integral membrane proteins) and membranes (which include normative bilipid membranes, non-lipid membranes and chemically-augmented bilipid membranes), and b.) the artificial synthesis of biological analogues of ion-channels, ion-pumps and membranes, which are structurally and chemically equivalent to naturally-occurring biological components but which are synthesized artificially – and applying such technologies and techniques toward the purpose the gradual replacement of our existing biological neurons constituting our nervous systems – or at least those neuron-populations that comprise the neo- and prefrontal-cortex, and through iterative procedures of gradual replacement thereby achieving indefinite-longevity. There is still work to be done in determining the comparative advantages and disadvantages of various structural and functional (i.e. design) motifs, and in the logistics of implanting the iterative replacement or reconstitution of ion-channels, ion-pumps and sections of neuronal membrane in-vivo.
The conceptual schemes outlined in Concepts for Functional Replication of Biological Neurons [66], Gradual Neuron Replacement for the Preservation of Subjective-Continuity [67] and Wireless Synapses, Artificial Plasticity, and Neuromodulation [68] would constitute variations on the basic approach underlying this proposed, embryonic interdisciplinary field. Certain approaches within the fields of nanomedicine itself, particularly those approaches that constitute the functional emulation of existing cell-types, such as but not limited to Robert Freitas’s conceptual designs for the functional emulation of the red blood cell (a.k.a. erythrocytes, haematids) [69], i.e. the Resperocyte, itself should be seen as falling under the purview of this new approach, although not all approaches to Nanomedicine (diagnostics, drug-delivery and neuroelectronic interfacing) constitute the physical (i.e. electromechanical, kinetic and/or molecular physically-embodied) and functional emulation of biological cells.
The field of functionally-restorative medicine in general (and of nanomedicine in particular) and the field of supramolecular and organic chemistry converge here, where these technological, methodological, and experimental infrastructures developed in field of Synthetic Ion-Channels and Ion Channel Reconstitution can be employed to develop a new interdisciplinary approach that applies the logic of prosthesis to the cellular and cellular-component (i.e. sub-cellular) scale; same tools, new use. These techniques could be used to iteratively replace the components of our neurons as they degrade, or to replace them with more robust systems that are less susceptible to molecular degradation. Instead of repairing the cellular DNA, RNA and protein transcription and synthesis machinery, we bypass it completely by configuring and integrating the neuronal components (ion-channels, ion-pumps and sections of bilipid membrane) directly.
Thus I suggest that theoreticians of nanomedicine look to the large quantity of literature already developed in the emerging fields of synthetic ion-channels and membrane-reconstitution, towards the objective of adapting and applying existing technologies and methodologies to the new purpose of iterative maintenance, upkeep and/or replacement of cellular (and particularly neuronal) constituents with either non-biological analogues or artificially-synthesized-but-chemically/structurally-equivalent biological analogues.
This new sub-field of Synthetic Biology needs a name to differentiate it from the other approaches to Functionally-Restorative Medicine. I suggest the designation ‘cellular prosthesis’.
References:
[1] Williams (1994)., An introduction to the methods available for ion channel reconstitution. in D.C Ogden Microelectrode techniques, The Plymouth workshop edition, CambridgeCompany of Biologists.
[2] Tomich, J., Montal, M. (1996). U.S Patent No. 5,16,890. Washington, DC: U.S. Patent and Trademark Office.
[69] Freitas Jr., R., (1998). “Exploratory Design in Medical Nanotechnology: A Mechanical Artificial Red Cell”. Artificial Cells, Blood Substitutes, and Immobil. Biotech. (26): 411–430. Access: http://www.ncbi.nlm.nih.gov/pubmed/9663339
In rich countries, more than 80% of the population today will survive past the age of 70. About 150 years ago, only 20% did. In all this while, though, only one person lived beyond the age of 120. This has led experts to believe that there may be a limit to how long humans can live.
Animals display an astounding variety of maximum lifespan ranging from mayflies and gastrotrichs, which live for 2 to 3 days, to giant tortoises and bowhead whales, which can live to 200 years. The record for the longest living animal belongs to the quahog clam, which can live for more than 400 years.
If we look beyond the animal kingdom, among plants the giant sequoia lives past 3000 years, and bristlecone pines reach 5000 years. The record for the longest living plant belongs to the Mediterranean tapeweed, which has been found in a flourishing colony estimated at 100,000 years old.
This jellyfish never dies. Michael W. May
Some animals like the hydra and a species of jellyfish may have found ways to cheat death, but further research is needed to validate this.
The natural laws of physics may dictate that most things must die. But that does not mean we cannot use nature’s templates to extend healthy human lifespan beyond 120 years.
Putting a lid on the can
Gerontologist Leonard Hayflick at the University of California thinks that humans have a definite expiry date. In 1961, he showed that human skin cells grown under laboratory conditions tend to divide approximately 50 times before becoming senescent, which means no longer able to divide. This phenomenon that any cell can multiply only a limited number of times is called the Hayflick limit.
Since then, Hayflick and others have successfully documented the Hayflick limits of cells from animals with varied life spans, including the long-lived Galapagos turtle (200 years) and the relatively short-lived laboratory mouse (3 years). The cells of a Galapagos turtle divide approximately 110 times before senescing, whereas mice cells become senescent within 15 divisions.
The Hayflick limit gained more support when Elizabeth Blackburn and colleagues discovered the ticking clock of the cell in the form of telomeres. Telomeres are repetitive DNA sequence at the end of chromosomes which protects the chromosomes from degrading. With every cell division, it seemed these telomeres get shorter. The result of each shortening was that these cells were more likely to become senescent.
Other scientists used census data and complex modelling methods to come to the same conclusion: that maximum human lifespan may be around 120 years. But no one has yet determined whether we can change the human Hayflick limit to become more like long-lived organisms such as the bowhead whales or the giant tortoise.
What gives more hope is that no one has actually proved that the Hayflick limit actually limits the lifespan of an organism. Correlation is not causation. For instance, despite having a very small Hayflick limit, mouse cells typically divide indefinitely when grown in standard laboratory conditions. They behave as if they have no Hayflick limit at all when grown in the concentration of oxygen that they experience in the living animal (3–5% versus 20%). They make enough telomerase, an enzyme that replaces degraded telomeres with new ones. So it might be that currently the Hayflick “limit” is more a the Hayflick “clock”, giving readout of the age of the cell rather than driving the cell to death.
The trouble with limits
Happy last few days? It doesn’t have to end this way. ptimat
The Hayflick limit may represent an organism’s maximal lifespan, but what is it that actually kills us in the end? To test the Hayflick limit’s ability to predict our mortality we can take cell samples from young and old people and grow them in the lab. If the Hayflick limit is the culprit, a 60-year-old person’s cells should divide far fewer times than a 20-year-old’s cells.
But this experiment fails time after time. The 60-year-old’s skin cells still divide approximately 50 times – just as many as the young person’s cells. But what about the telomeres: aren’t they the inbuilt biological clock? Well, it’s complicated.
When cells are grown in a lab their telomeres do indeed shorten with every cell division and can be used to find the cell’s “expiry date”. Unfortunately, this does not seem to relate to actual health of the cells.
It is true that as we get older our telomeres shorten, but only for certain cells and only during certain time. Most importantly, trusty lab mice have telomeres that are five times longer than ours but their lives are 40 times shorter. That is why the relationship between telomere length and lifespan is unclear.
Apparently using the Hayflick limit and telomere length to judge maximum human lifespan is akin to understanding the demise of the Roman empire by studying the material properties of the Colosseum. Rome did not fall because the Colosseum degraded; quite the opposite in fact, the Colosseum degraded because the Roman Empire fell.
Within the human body, most cells do not simply senesce. They are repaired, cleaned or replaced by stem cells. Your skin degrades as you age because your body cannot carry out its normal functions of repair and regeneration.
To infinity and beyond
If we could maintain our body’s ability to repair and regenerate itself, could we substantially increase our lifespans? This question is, unfortunately, vastly under-researched for us to be able to answer confidently. Most institutes on ageing promote research that delays onset of the diseases of ageing and not research that targets human life extension.
Those that look at extension study how diets like calorie restriction affect human health or the health impacts of molecules like resveratrol derived from red wine. Other research tries to understand the mechanisms underlying the beneficial effects of certain diets and foods with hopes of synthesising drugs that do the same. The tacit understanding in the field of gerontology seems to be that, if we can keep a person healthy longer, we may be able to modestly improve lifespan.
Living long and having good health are not mutually exclusive. On the contrary, you cannot have a long life without good health. Currently most ageing research is concentrated on improving “health”, not lifespan. If we are going to live substantially longer, we need to engineer our way out of the current 120-year-barrier.
Avi Roy does not work for, consult to, own shares in or receive funding from any company or organisation that would benefit from this article, and has no relevant affiliations.
The following article was originally published by Immortal Life
When asked what the biggest bottleneck for Radical or Indefinite Longevity is, most thinkers say funding. Some say the biggest bottleneck is breakthroughs and others say it’s our way of approaching the problem (i.e. that we’re seeking healthy life extension whereas we should be seeking more comprehensive methods of indefinite life-extension), but the majority seem to feel that what is really needed is adequate funding to plug away at developing and experimentally-verifying the various, sometimes mutually-exclusive technologies and methodologies that have already been proposed. I claim that Radical Longevity’s biggest bottleneck is not funding, but advocacy.
This is because the final objective of increased funding for Radical Longevity and Life Extension research can be more effectively and efficiently achieved through public advocacy for Radical Life Extension than it can by direct funding or direct research, per unit of time or effort. Research and development obviously still need to be done, but an increase in researchers needs an increase in funding, and an increase in funding needs an increase in the public perception of RLE’s feasibility and desirability.
There is no definitive timespan that it will take to achieve indefinitely-extended life. How long it takes to achieve Radical Longevity is determined by how hard we work at it and how much effort we put into it. More effort means that it will be achieved sooner. And by and large, an increase in effort can be best achieved by an increase in funding, and an increase in funding can be best achieved by an increase in public advocacy. You will likely accelerate the development of Indefinitely-Extended Life, per unit of time or effort, by advocating the desirability, ethicacy and technical feasibility of longer life than you will by doing direct research, or by working towards the objective of directly contributing funds to RLE projects and research initiatives. Continue reading “Longevity’s Bottleneck May Be Funding, But Funding’s Bottleneck is Advocacy & Activism” | >
It is often said that empiricism is one of the most useful concepts in epistemology. Empiricism emphasises the role of experience acquired through one’s own senses and perceptions, and is contrary to, say, idealism where concepts are not derived from experience, but based on ideals.
In the case of radical life extension, there is a tendency to an ‘idealistic trance’ where people blindly expect practical biotechnological developments to be available and applied to the public at large within a few years. More importantly, idealists expect these treatments or therapies to actually be effective and to have a direct and measurable effect upon radical life extension. Here, by ‘radical life extension’ I refer not to healthy longevity (a healthy life until the age of 100–120 years) but to an indefinite lifespan where the rate of age-related mortality is trivial.
Let me mention two empirical examples based on experience and facts:
1. When a technological development depends on technology alone, its progress is often dramatic and exponential.
2. When a technological development also depends on biology, its progress is embarrassingly negligible.
Developments based solely on mechanical, digital or electronic concepts are proliferating freely and vigorously. Just 20 years ago, almost nobody had a mobile telephone or knew about the internet. Now we have instant global communication accessible by any member of the general public.
Contrast this with the advancement of biotechnology with regards to, say, the treatment of the common cold. There has not been a significantly effective treatment for the public at large for, I will not say a million, but certainly for several thousand years. The accepted current medical treatment for the common cold is with bed rest, fluids, and antipyretics which is the same as that suggested by Hippocrates. Formal guidelines for the modern treatment of cardiac arrest include chest compressions and mouth- to- mouth resuscitation (essentially the same as the technique used by the prophet Elisha in the Old Testament) as well as intra-cardiac (!) atropine, lignocaine and other drugs used by physicians during the 1930’s. In my medical museum in Cyprus (http://en.wikipedia.org/wiki/Kyriazis_Medical_Museum) I have examples of Medieval treatments for urinary retention (it was via a metal urinary catheter then, whereas now the catheter is plastic), treatment of asthma (with belladonna then, ipratropium now – a direct derivative), and treatment of pain (with opium then, with opium-like derivatives now).
About a hundred years ago, my grandfather (http://en.wikipedia.org/wiki/Neoklis_Kyriazis) wrote a book on hygiene, longevity and healthy life for the public, which included advice such as fresh air, exercise, consumption of fruit and vegetables, avoidance of excessive alcohol or cigarette smoke. These are of course preventative treatments advised by modern anti-ageing practitioners, hardly any progress in a century. In fact, these are the only proven treatments. Even the modern notion of ‘antioxidants’ can be encountered as standard health advice in medical books from the 1800’s. With the trivial exception of a handful of other examples, there has hardly been any progress in healthy longevity at all that can be applied to the common man in the street. Resveratrol? Was a standard health advice in ancient Greek medicine (red wine). Carnosine? Discovered and used 100 years ago. Cycloastragenol? Used in Chinese medicine 1000 years ago.
My question is: how do we expect to influence the process of ageing when we cannot even develop bio-technological cures for simple and common diseases? Are we really serious when we talk about biotechnological treatments that can lead to radical life extension, being developed within the next few years? And if we are really serious, is this belief based on empiricism or idealism? The manipulation of human biology has been particularly tricky, with no significant progress of effective breakthroughs developed during the past several decades. Here I, of course, acknowledge the value of some modern drugs and isolated bio-technological achievements, but my point is that these developments are based on relatively minor refinements of existing therapies, and not on new breakthroughs that can modify the human body in any positive or practical degree. Importantly, even if some isolated examples of effective biotechnology do exist, these are not yet suitable for use by the general public at large.
If we were to compare the progress of general technology with that of life extension biotechnology, we could see that:
A. The progress of technology over the past 100 years has been logarithmic to exponential, whereas that of life extension biotechnology has been virtually static.
B. The progress of technology over the past 20 years has been exponential, whereas that of life extension biotechnology has barely been logarithmic.
It is one thing to talk about future biotechnology developments as a discussion point, and to post these in blogs, for general curiosity. But it is a different thing altogether if we actually want to devise and deliver an effective, practical therapy that truly affords significant life extension.
A different approach is needed, one that does not depend exclusively on biotechnology. It would be naïve to say that I am arguing for the total abandonment of life extension biotechnology, but it is equally naïve to believe that this biotechnology is likely to be effective on its own. A possible way forward could be the attempt to modify human biology not via biotechnology alone, but also by making use of natural, already existing evolutionary mechanisms. One such example could be the use of ‘information-that-requires-action’ in order to force a reallocation of resources from germ-line to somatic cells. This is an approach we currently aiming to describe in detail. My final remark with regards to achieving indefinite lifespan is this: we must engage with technology without depending on biotechnology.
For some general background information on how to engage with technology see:
Freedom fironically found in flesh, not knowing whe’er I’m foul or fowl… tickly bound neath trickly form twisting and more unfresh as dawn upon dawn dies in menstrual skyfire like blood made light — a mocking microcosm of my own transubstantiation from rotting viscera to lightstorm infinity?
Just what sick joke is this? To wake and ache and dream and be and become! – and then to die..? To culminate the very universe itself!.. and then to simply die?! For what I ask you! What! Death… what audacious greed! What reckless squander and heedless extravagance!
Guttural red fringed black a bulbous muck death bastphelgmy! We cannot comprehend the sheer stature of death and so hurriedly cover the unknown with a word to hold it in hand and at a distance, to doubt no doubt.
O pallid heavens! O incessant sun undaunted by my barrenaked finitude! O fetid sanctity wet and redragged as the sickly bloom of jagged flesh! O putrid night sky serene despite my spat fury; as I ebb and ember a’roil withinside my sadness unbelieving and hysteric animal heat that vile sun and auster night jaunt their jeer and mock the rude squall of my panicstrewn death nonetheless.
We must not believe them when they tell us with sad care that we will one day die.
We must not believe them when they tell us that we will escape death by any means but our own daring.
We must bleed our eschaton passion upforth and afroth upon that void hated with awefull grandeur for its monster honesty. We must take self in hand and be/hold the possible futures still fetal inside. We must rage our righteous revolt with pride bright as that unsickened sun, not afraid to boast that we fear death but instead eager to thrust our fervent urgency upon the others still bound to opiate incredulity.
We are Man, and we shall NOT go quietly into that dog night!
1. Thou shalt first guard the Earth and preserve humanity.
Impact deflection and survival colonies hold the moral high ground above all other calls on public funds.
2. Thou shalt go into space with heavy lift rockets with hydrogen upper stages and not go extinct.
The human race can only go in one of two directions; space or extinction- right now we are an endangered species.
3. Thou shalt use the power of the atom to live on other worlds.
Nuclear energy is to the space age as steam was to the industrial revolution; chemical propulsion is useless for interplanetary travel and there is no solar energy in the outer solar system.
4. Thou shalt use nuclear weapons to travel through space.
Physical matter can barely contain chemical reactions; the only way to effectively harness nuclear energy to propel spaceships is to avoid containment problems completely- with bombs.
5. Thou shalt gather ice on the Moon as a shield and travel outbound.
The Moon has water for the minimum 14 foot thick radiation shield and is a safe place to light off a bomb propulsion system; it is the starting gate.
6. Thou shalt spin thy spaceships and rings and hollow spheres to create gravity and thrive.
Humankind requires Earth gravity and radiation to travel for years through space; anything less is a guarantee of failure.
7. Thou shalt harvest the Sun on the Moon and use the energy to power the Earth and propel spaceships with mighty beams.
8. Thou shalt freeze without damage the old and sick and revive them when a cure is found; only an indefinite lifespan will allow humankind to combine and survive. Only with this reprieve can we sleep and reach the stars.
9. Thou shalt build solar power stations in space hundreds of miles in diameter and with this power manufacture small black holes for starship engines.
10. Thou shalt build artificial intellects and with these beings escape the death of the universe and resurrect all who have died, joining all minds on a new plane.
The Brain Games Begin Europe’s billion-Euro science-neuro Human Brain Project, mentioned here amongst machine morality last week, is basically already funded and well underway. Now the colonies over in the new world are getting hip, and they too have in the works a project to map/simulate/make their very own copy of the universe’s greatest known computational artifact: the gelatinous wad of convoluted electrical pudding in your skull.
The (speculated but not yet public) Brain Activity Map of America About 300 different news sources are reporting that a Brain Activity Map project is outlined in the current administration’s to-be-presented budget, and will be detailed sometime in March. Hoards of journalists are calling it “Obama’s Brain Project,” which is stoopid, and probably only because some guy at the New Yorker did and they all decided that’s what they had to do, too. Or somesuch lameness. Or laziness? Deference? SEO?
For reasons both economic and nationalistic, America could definitely use an inspirational, large-scale scientific project right about now. Because seriously, aside from going full-Pavlov over the next iPhone, what do we really have to look forward to these days? Now, if some technotards or bible pounders monkeywrench the deal, the U.S. is going to continue that slide toward scientific… lesserness. So, hippies, religious nuts, and all you little sociopathic babies in politics: zip it. Perhaps, however, we should gently poke and prod the hard of thinking toward a marginally heightened Europhobia — that way they’ll support the project. And it’s worth it. Just, you know, for science.
Going Big. Not Huge, But Big. But Could be Massive. Both the Euro and American flavors are no Manhattan Project-scale undertaking, in the sense of urgency and motivational factors, but more like the Human Genome Project. Still, with clear directives and similar funding levels (€1 billion Euros & $1–3 billion US bucks, respectively), they’re quite ambitious and potentially far more world changing than a big bomb. Like, seriously, man. Because brains build bombs. But hopefully an artificial brain would not. Spaceships would be nice, though.
Practically, these projects are expected to expand our understanding of the actual physical loci of human behavioral patterns, get to the bottom of various brain pathologies, stimulate the creation of more advanced AI/non-biological intelligence — and, of course, the big enchilada: help us understand more about our own species’ consciousness.
On Consciousness: My Simulated Brain has an Attitude? Yes, of course it’s wild speculation to guess at the feelings and worries and conundrums of a simulated brain — but dude, what if, what if one or both of these brain simulation map thingys is done well enough that it shows signs of spontaneous, autonomous reaction? What if it tries to like, you know, do something awesome like self-reorganize, or evolve or something?
Maybe it’s too early to talk personality, but you kinda have to wonder… would the Euro-Brain be smug, never stop claiming superior education yet voraciously consume American culture, and perhaps cultivate a mild racism? Would the ‘Merica-Brain have a nation-scale authority complex, unjustifiable confidence & optimism, still believe in childish romantic love, and overuse the words “dude” and “awesome?”
The Golden Rule is Not for Toasters Simplistically nutshelled, talking about machine morality is picking apart whether or not we’ll someday have to be nice to machines or demand that they be nice to us.
Well, it’s always a good time to address human & machine morality vis-à-vis both the engineering and philosophical issues intrinsic to the qualification and validation of non-biological intelligence and/or consciousness that, if manifested, would wholly justify consideration thereof.
Uhh… yep!
But, whether at run-on sentence dorkville or any other tech forum, right from the jump one should know that a single voice rapping about machine morality is bound to get hung up in and blinded by its own perspective, e.g., splitting hairs to decide who or what deserves moral treatment (if a definition of that can even be nailed down), or perhaps yet another justification for the standard intellectual cul de sac: “Why bother, it’s never going to happen.“ That’s tired and lame.
One voice, one study, or one robot fetishist with a digital bullhorn — one ain’t enough. So, presented and recommended here is a broad-based overview, a selection of the past year’s standout pieces on machine morality.The first, only a few days old, is actually an announcement of intent that could pave the way to forcing the actual question. Let’s then have perspective:
Building a Brain — Being Humane — Feeling our Pain — Dude from the NYT • February 3, 2013 — Human Brain Project: Simulate One Serious Euro-Science to simulate a human brain. Will it behave? Will we?
• January 28, 2013 — NPR: No Mercy for Robots A study of reciprocity and punitive reaction to non-human actors. Bad robot.
Even now should someone attempt to smash your smartphone or laptop (or just touch it), you of course protect the machine. Extending beyond concerns over the mere destruction of property or loss of labor, could one morally abide harm done to one’s marginally convincing humanlike companion? Even if fully accepting of its artificiality, where would one draw the line between economic and emotional damage? Or, potentially, could the machine itself abide harm done to it? Even if imbued with a perfectly coded algorithmic moral code mandating “do no harm,” could a machine calculate its passive non-response to intentional damage as an immoral act against itself, and then react?
Yeah, these hypotheticals can go on forever, but it’s clear that blithely ignoring machine morality or overzealously attempting to engineer it might result in… immorality.
Probably Only a Temporary Non-Issue. Or Maybe. Maybe Not. There’s an argument that actually needing to practically implement or codify machine morality is so remote that debate is, now and forever, only that — and oh wow, that opinion is superbly dumb. This author has addressed this staggeringly arrogant species-level macro-narcissism before (and it was awesome). See, outright dismissal isn’t a dumb argument because a self-aware machine or something close enough for us to regard as such is without doubt going to happen, it’s dumb because 1. absolutism is fascist, and 2. to the best of our knowledge, excluding the magic touch of Jesus & friends or aliens spiking our genetic punch or whatever, conscious and/or self-aware intelligence (which would require moral consideration) appears to be an emergent trait of massively powerful computation. And we’re getting really good at making machines do that.
Whatever the challenge, humans rarely avoid stabbing toward the supposedly impossible — and a lot of the time, we do land on the moon. The above mentioned Euro-project says it’ll need 10 years to crank out a human brain simulation. Okay, respectable. But, a working draft of the human genome, an initially 15-year international project, was completed 5 years ahead of schedule due largely to advances in brute force computational capability (in the not so digital 1990s). All that computery stuff like, you know, gets better a lot faster these days. Just sayin.
So, you know, might be a good idea to keep hashing out ideas on machine morality. Because who knows what we might end up with…
“Oh sure, I understand, turn me off, erase me — time for a better model, I totally get it.“ - or - “Hey, meatsack, don’t touch me or I’ll reformat your squishy face!”
I recently posted this on the only two other sites that will allow me to express my opinions;
I see the problem as one of self similarity; trying to go cheap being the downfall of all these schemes to work around human physiology.
When I first became interested in space travel several years ago I would comment on a couple blogs and find myself constantly arguing with private space proponents- and saying over and over again, “there is no cheap.” I was finally excommunicated from that bunch and banned from posting. They would start calling me an idiot and other insults and when I tried to return the favor the moderator would block my replies. The person who runs those two sites works for a firm promoting space tourism- go figure.
The problem is that while the aerospace industry made some money off the space program as an outgrowth of the military industrial complex, it soon became clear that spaceships are hard money- they have to work. The example of this is the outrage over the Apollo 1 fire and subsequent oversight of contractors- a practice which disappeared after Apollo and resulted in the Space Shuttle being such a poor design. A portion of the shuttle development money reportedly went under the table into the B-1 bomber program; how much we will never know. Swing wings are not easy to build which is why you do not see it anymore; cuts into profits.
The easy money of cold war toys has since defeated any move by industry to take up the cause of space exploration. No easy money in spaceships. People who want something for nothing rarely end up with anything worth anything. Trying to find cheap ways around furnishing explorers with the physcial conditions human beings evolved in is going to fail. On the other hand if we start with a baseline of one gravity and Earth level radiation we are bound to succeed.
The engineering solutions to this baseline requirement are as I have already detailed; a tether for gravity and a massive moonwater shield with bomb propulsion. That is EXACTLY how to do it and I do not see any one else offering anything else that will work- just waffling and spewing about R&D. We have been doing R&D for over half a century. It is a reason to go that is supposedly lacking.
When that crater in Mexico was discovered in 1980 the cold war was reaching it’s crescendo and the massive extinction it caused was overshadowed by the threat of nuclear weapons. Impact defense is still the only path to all that DOD money for a Moon base.
