Things that correlate with lifespan
To couteract aging it might be helpful to consider things that correlate with lifespan, especially if they can be influenced externally.
Anti-Ageing Drugs/Substances
As about 90% of all free radicals are produced in the mitochondria and there is good evidence that the rate of free radical production correlates inversely with lifespan, one good ansatz seems to be to target anti-oxidants to mitochondria.
Catalytic antioxidants: a radical approach to new therapeutic
Nitrones:
Nitrones caught my attention because there have been experiments with a substance called LPBNAH, which extended the lifespan of rotifiers by around 250% !!! LPBNAH is derived from a quite well known substance called PBN (see below), which has been shown to extend life span in two mouse and in one rat model. Therefore one might speculate that LPBNAH is capable of yielding similarly spectacular life extension effects in mice or in humans.
Mitochondrial medicine: neuroprotection and life extension by the new amphiphilic nitrone LPBNAH acting as a highly anioxidant agent - „…Remarkable gerontoprotective effect of LPBNAH are demonstrated after chronic administration …with extension of mean and maximal lifespan by more than 250%, indicating that this amphiphilic antioxidant agent is far superior to all other previously tested antioxidant compounds and at least one order of magnitude more potent than any previously documented anti-ageing strategies…".
Nitrones, their value as therapeutics and probes to understand aging - "alpha-phenyl-tert-butyl-nitrone (PBN), has been shown to extend life span in three published studies, i.e. two mouse models and one rat model. ...a novel nitrone, CPI-1429, which demonstrated the ability to extend life span even though administration of the compound was begun in older animals."
Nitrones as Neuroprotectants and Antiaging Drugs
A spin trap, N-tert-butyl-alpha-phenylnitrone extends the life span of mice
SOD mimetics:
A carboxyfullerene SOD mimetic improves cognition and extends the lifespan of mice - "Chronic treatment not only reduced age-associated oxidative stress and mitochondrial radical production, but significantly extended lifespan. ... demonstration that an administered antioxidant with mitochondrial activity and nervous system penetration not only increases lifespan, but rescues age-related cognitive impairment in mammals."
Extension of Life-Span with Superoxide Dismutase/Catalase Mimetics
Polyphenols
Blueberry polyphenmols increase lifespan and thermotolerance in Caenorhabditis elegans
Sirtuin activators mimic caloric restriction and delay ageing in metazoans - Interesting findings about how calorie restriction and resveratrol work and about their interplay.
Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan
Antidiabetics
Insulin and longevity: antidiabetic biguanides as geroprotectors
Carnosine
Calorie Restriction
Research
Calorie restriction is a very robust method to extend mean and maximum lifespan, which has been shown to work in many species (e.g. yeast, nematodes, fruit flies, mice, water fleas, spiders, fish, dogs). It therefore is a very important tool to study ageing.
Effects of diet restriction on life span and age-related changes in dogs
Preliminary results indicate that calorie restriction also extends lifespan in monkeys. It therfore it is quite likely, that it also works in humans.
Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency - "Our results provide definitive evidence of a major cellular change in which CR induces a greater number of more efficient mitochondria."
Mitochondrial and nuclear DNA base excision repair are affected differently by caloric restriction - "CR appears to promote mitochondrial genomic stability largely by reducing mitochondrial ROS production."
Does it work in humans ?
It probably works in humans as well as in other species tested so far, but the question is how big will the effect be in comparison. The jury is still out, but let's do some speculations:
- A different lifespan extension effect has been observed in different species and there seems to be a tendency for bigger effects in smaller and more short lived species.
- If a lifespan extension of e.g. 40% were possible like it has been seen in some species, the maximum lifespan for humans would be around 170 years. There would probably be epidemiological data available, exhibiting people with ages beyond 120 years. Nothing of this kind has been seen so far except for anectdotes (interestingly with the longer the lifespans the later they date back). All it would take is to eat less (which definitely occurs, see. e.g. Okinawans, religious/spiritual people) and to get an adequate amount of the relevant nutrients (which often doesn't happen but is most likely not to be the case for all people that eat less).
- Humans are one of the most optimized species on the planet like birds and bats (see maintenance factors above). As calorie restriction seems to trigger a genetic switch that leads to improved maintenance (DNA-repair, detoxification, production of heat shock proteins, cell cycle arrest, shut down of reproduction, ...) there might not be so much maintenance potential left over as in other animals.
- For a mouse for example there is a selection pressure to be able to survive times of food shortage as those last typically of the order of a lifespan of the mouse, say 1 year. If the mouse can survive this time it can be fecundant again. For a mouse 1 year is a big percentage of its lifespan, for long lived species like humans it is not. (E.i. the longer lived species are the less evolution cares about them if calorie restriction works in them or not).
An excellent account on the "dark side" of calorie restriction in respect to its application in humans: Caloric Restriction for Longevity: I. Paradigm, Protocols and Physiological Findings in Animal Research, Caloric Restriction for Longevity: II The Systematic Neglect of Behavioural and Psychological Outcomes in Animal Research
Companies
Telomere Prolongation:
AGE Breakers:
Stem Cell Therapy:
SuperOxide Dismutase/Catalase Mimetics:
CR mimetics:
The disadvantage of the following drugs is, that they are anti-metabolics, i.e. one can eat as much as one wants and doesn't feel hungry, however energy expentiture is still reduced (one is put on a weak form of hybernation, biological processes are slowed down: silencing of genes) and one feels weaker, which is in my opinion the big problem with calorie restriction.
Sports and ageing
Lifelong voluntary exercise in the mouse prevents age-related alterations in gene expression in the heart
Beneficial effects of moderate exercise on mice aging: survival, behavior, oxidative stress, and mitochondrial electron transfer
Supplements
WHAT MITOCHONDRIA SUBSTANCES MAY REDUCE THE RATE OF AGING AND INCREASE ENDURANCE PERFORMANCE
Whey:
Whey Protein and Life-Extension - "showed a 30% increase in mean survival time of whey-fed mice...". Hamsters fed 20 % lactalbumin (whey) showed a lifespan increase of 52% in males and 46% in females.
The Life Extension Protein - "The Canadian scientists believe that the glutathione- and immune-boosting activity of whey protein depends largely upon glutamylcysteine peptides contained in its serum albumin fractions, in the betalactoglobulin, and possibly in the immunoglobulin G fraction. They believe it is critically important to preserve the structure of these glutamylcysteine peptides in order to maintain the integrity of the protein. If the glutamylcysteine peptides unfold, they expose it to digestive enzymes which destroy its integrity and rob it of its health-building properties."
Glutathione is endogenously synthesized in two steps:
1.) Cysteine + Glutamate --> Gamma-Glutamyl-Cysteine (GGC)
2.) GGC + Glycine --> Glutathione
Reaction 1.) is catalized by glutamate-cysteine ligase which is the rate-limiting reaction. Glutathione is exclusively synthesized in the cytosol and part of it is transported into the mitochondria.
Overexpression of Glutamate-Cysteine Ligase Extends Life Span in Drosophila melanogaster
Orally administered glutathione is not transported into the cells, GGC however is.
One might therefore speculate that administration of (undenaturated!) whey, i.e. glutamylcysteine leads to an extension of human lifespan.
There is a company in Australia that is supposed to offer glutamylcysteine as an anti-aging drug (see New glutathione source hails from Australia).
Melatonin:
Pineal control of aging: effect of melatonin and pineal grafting on aging mice
Vitamin E:
This result should be taken with caution in respect to humans, because there is also a metastudy out there concluding, that high doses of Vit. E shorten lifespan in humans:
Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality
Alpha Lipoic Acid:
Influence of selegiline and lipoic acid on the life expectancy of immunosuppressed mice - "The racemate of lipoic acid at high dosage (350 mg/kg body weight) reduced the life span significantly....whereas the physiologic R(+)-enantiomer (9 mg/kg body weight) expanded the total life span of its group."
Nutrition
COCOA POLYPHENOLS BENEFIT LONGEVITY - "... lifespan of rats consuming chocolatier Barry Callebaut’s ACTICOA cocoa polyphenol powder was 30 per cent longer than that of rats subjected to the same stress levels without being given cocoa polyphenols. ... ACTICOA chocolate is now the richest natural source of antioxidants, containing a much higher polyphenol concentration than red wine or green tea."
Dietary Soybean Protein Compared with Casein Retards Senescence in the Senescence Accelerated Mouse
... TODO beans ...
Cancer
Small Molecule Offers Big Hope Against Cancer
Sleep
Experts challenge study linking sleep, life span
Therapies
If there is a way to fundamentally prolong lifespan, a good starting point start with is a model organism, as these animals are well known. A good example is Caenerhabditis elegans, which consists of about 1000 cells. These are postmitotic cells so the problem is ...
MtDNA replacement:
Institute on Aging at the University of Virginia - "...we have developed a novel technology that allows the removal of damaged mitochondrial DNA and its replacement with healthy mitochondrial DNA."
Balingen, 01.09.06 home@markus-maute.de (Comments are always welcome)
