As was discussed in the last article (and 4, 5), the environment clearly affects longevity. For example, the presence of extrinsic mortality factors- like food scarcity, predators, and cold - influence the longevity of the species.. In many instances, given a high mortality in early life, a harsh environment will  move animals to an earlier reproductive phase with high fecundity and faster aging (5). In other words, the species will reproduce much faster at early ages to accommodate higher mortality rates.

Interestingly, however, animals  that seem to adapt to their harsh environments - particularly when they have the ecological advantage of escaping predators - will tend to develop longer lifespans. Thus, flying and subterranean animals tend to be longer-lived (4).

Experimentally, subjecting animals to a harsh environment for short intervals does indeed support its benefit as an anti-aging mechanism: 

• Calorie restriction: When rats eat 30% less, they live longer lives - sometimes up to 45% longer (6)
• cold: flies raised at  18 °C lived 148 days versus flies raised at 12 °C lived 247 days, 66% longer lifespan (7).
• Hypoxia: Mice exposed to chronic hypoxia for ~ 1 month showed gene expression patterns of animals that underwent calorie restriction; Flies (Drosophila) lived 17% longer lives under moderate hypoxic conditions (4, 8)

Let's see what effect manipulating genes has on longevity. 

Certain species of animals seem to be born with the right genes. They don't only live 17-66% longer, as shown above, they live several fold longer: 200 - 1000%! For example:

• Birds - as a general rule - live 2 - 3 times as long as mammals the same size (9). Larger birds live longer lives; for example, large parrots - like Macaws - have been known to live up to 100 years. 
• Naked mole rats live 30+ years - 5 times when compared to similar sized rodents (10)
•  Naked mole rats live 4 times longer than the North American pika (a rodent very close to rabbits)very similar body sizes) (11). Interestingly the body temperature of the Naked mole rat is 32.1 °C ( 89.8 °F) versus the North American pika at 40.1 °C ( 104.2 °F).
• Whales live a long time. But one species of whales - the Bowhead whale - beats its close cousins by living 2 times as long. 
• Bats live 3.5 times greater than a non-flying placental mammal of similar size (12)
• Mussels that have adapted to the cold temperatures of arctic Russian rives live 5 x times longer than the same species of freshwater pearl mussels that live in the warmer rivers in Spain (13). 
• Salamanders (Class Amphibia) are lizard-like animals, but basically are related to frogs and toads who are also amphibians. Frogs and toads live 4 - 9 years; salamanders can live from 20 - 100 years (14) or 5 - 10 times longer.
• Turtles barely age compared to humans. Turtles have this incredible ability to live long lives(15) with some Tortoises documented to living almost 200 years. Their closest relative are crocodiles  that have a lifespan of 70 years. This means turtles have lifespans that are almost 3 times as long. 

Calorie restriction, living in hypoxic conditions (for example, like Tibetans), exercise all prolong life and well-being but not at the level of 2 - 10 times as long. 

It is fascinating that many - if not most - of the species described above have managed to inherit an ecological advantage. This seemed to allow them to garner an additional advantage in their genes that facilitated longevity. This model is called the adaptive hitchhike model (4).

Thus, birds developed flight to give them an edge on survival. With that, they had to have a high metabolic rate. On the way, they accumulated genes that protect the cell from oxidative damage that can ensue from high metabolic rates. Lower oxidative damage equates to longer lifespans. 

In the same vein, arctic animals adapted to frigid waters; this also helped their cells accentuate genes that promoted cellular longevity.

When studying animals with unusually long lives, a pattern emerges:  there are major changes in genes  that generate proteins that serve as critical pathways in the cell. For example, genes related to the IGF1 Receptor, oxidative change, cellular stress response, and DNA repair contribute to longevity (16, 17).

Why is this important? because it suggests that there are inbuilt systems that promote or discourage aging from the time we are born. 

Manipulating genes and proteins can force the nucleus to do things differently. Sometimes the result is negative (the cell dies) but other times, there is a marked improvement in the health of the cell and - more importantly- a reversal of the aging markers within the cell (18, 19, 20).

For example, Induced expression of specific transcription factors in the nucleus can activate youth- inducing genes. In experiments on the eyes of mice, retinal ganglion cells showed that 90% of the genes were restored to youthful levels by injection those transcription factors into the vitreous of old mice. Incredibly,  there was a restoration of visual acuity in 12-months old mice (18).

In addition, some drugs (metformin, rapamycin, nicotinamide, resveratrol) have been used to generate downstream effects at the level of the nucleus, activating genes that promote longevity (aka, epigenetic reprogramming) (19).

In effect, even old cells can be brought back to some semblance of youthfulness. The challenge is doing without causing deleterious effects, such as induction of cancerous change or drug toxicity.

It could be that anti-aging therapeutics will be based on a combination of age-reducing mechanisms: Encouraging youthfulness in the nucleus, decreasing cytoplasmic junk (autophagy), and destroying senescent cells (21).

Rejuvenating the nuclear makeup of the cell will need to be a critical part of any anti-aging therapy, given the key role of epigenetic reprogramming. However, it is also important to understand that animals that have extreme longevity are not only blessed with that element. They also have: 

• Prolonged youthfulness
• Extended fertility 
• Resistance to cancer

A whole package in one, just because they were in the right place at the right time. In the next series of articles, I will discuss the value of keeping one's stem cells young.