If mankind wants to live much longer, we will probably need to figure out the molecular phenomena behind aging and its characteristics. How cells in our body achieve homeostasis (in terms of cellular energy) is directly related to the lifespan of an organism. Efficient genetic engineering tools such as the CRISP-R/CAS-9 system, along with developing ideas for cryogenics could contribute to a major discovery for the school of longevity. But first, let’s explore the critical biological features that are required for this to work.
Minimal erroneous mutations and resilience against cancer
Not all mutations are bad. When it comes to the health and lifespan of organisms, mutations that result in an evolutionary advantage are desired. Specifically, we want mutations that increase the longevity of cells. For example, a study with mice showed that a targeted single point mutation achieved a remarkable 64% increase in its lifespan.
On the downside, mutations can also lead to physiological disorders and even diseases such as cancer. Aging is associated with an increase in the probability of cancer. Some of the key pathways that modulate cancer progression – and have been implicated in aging – are the growth hormone (GH), insulin-like growth factor 1(IGF-1), mechanistic target of rapamycin (mTOR), and the activation of AMP kinase (AMPK).
Theoretically, the risk of developing cancer increases with the number of cells and the lifespan of an organism. Thus, one would deduce that the larger an organism, the higher the chances of cancer occurrence. But that is not the case. It has been discovered that large mammals, e.g. humpback whales, are not more susceptible to cancer compared to humans. This is explained by the Peto Paradox which posits that there is a lack of correlation between size and the risk of cancer.
In addition, while lab mice seem more susceptible to cancer compared to humans cells, naked mole-rats (Heterocephalus glaber) that are similar in size to lab mice can live up to 32 years and rarely die of cancer. Also, elephants are one of the best examples of a species that has anti-cancer resilience.
Of all the molecular pathways mentioned above, if we could identify the one(s) that causes these differences, we could isolate the pathway(s) and extend the lifespan of humans.
Cytoskeletal integrity and cellular organisation
When we talk about organisms, we usually refer to the cells they are made of. An organism’s structural integrity and cellular resilience depend on its layers of phospholipid as well as biomolecules. This intricate network makes up the cytoskeleton, which is the “cell skeleton”.
While aging, cells accumulate all kinds of oddity caused by degeneration and stress on the cytoskeleton. For instance, geometric alterations in aging red blood cells may cause changes to their surface texture. Moreover, as cells age, signaling molecules in the cell membrane are dysregulated.
The extracellular matrix (ECM) is an important contributor to the health of a cell. Collagen is an ECM that is common in all species. In C. elegans (worm), the production of collagen decline with age, and collagen is essential for daf-2-mediated longevity. Meanwhile, in aging humans, glycosylation and proteomic damage to the ECM proteins are seen. This is especially frequent in patients with Type-2 diabetes.
Another factor that slows down aging is a lower degree of fatty acid unsaturation of cellular membranes in postmitotic tissues. In long-lived animals, the degree of fatty acid unsaturation in membranes provides this advantage by decreasing lipid peroxidation. From these observations, species-specific desaturation pathways that determine membrane composition, which in turn maintains an appropriate environment for membrane function, are present.
For the model organisms of C. elegans (worm) and Drosophila (fly), the insulin/IGF-1 signalling (IIS) pathway was one of the first pathways to make an impact on lifespan. In both species, there is a single receptor for IIS: daf-2 in C. elegans (worm) and InR in Drosophila (fly). Mutation of the receptor doubled the worm’s lifespan and increased lifespan by 85% in Drosophila, albeit for the dwarf phenotype.
In mammals, there are separate receptors for insulin and IGF-1. When insulin receptors (INSR) were knocked out in adipose tissue-specific mice, they lived 18% longer than wild-type mice. In humans, apart from the IGF1-R that is associated with extreme longevity, there are other genetic variations identified in long-living centenarians namely the FOXO3A and GHR. These genes exhibit polymorphism which is found to influence health and longevity in humans.
A few other pathways and proteins were discovered to be essential for extending lifespan. One such protein is from the Sirtuin (homologs of yeast Silent Information Regulator/SIR) family. In mammals, there are seven Sirtuin proteins (SIRT 1-7), and they are specific to the different aging cellular processes. In mice, the overexpression of SIRT6, as well as the localized overexpression of SIRT1 in the brain, extends lifespan. Sirtuin activity is also linked to a healthier metabolism, efficient DNA repair, and higher genetic stability.
Another signaling pathway that significantly affects lifespan across different species is the mTOR (mechanistic target of rapamycin). In model organisms including yeast, C.elegans (worms), Drosophila (flies), and mice, inhibiting mTOR extended lifespan. mTOR is associated with protein translation, autophagy stimulation, and integration of upstream signals from other related pathways such as AMPK, IIS, and PI3K. Long-lived species are hence expected to potentially exploit mTOR for proteostasis, cell growth control, and the lowering of cancer occurrence.
Hopes for the future
The examples provided here are the ones that have been studied the most. For continued inspiration, we should explore the cellular characteristics of organisms that have a naturally long lifespan or those that can withstand extreme environments. For instance, there is a lot to learn from long-living plants, unusual organisms like tardigrades (water bears), worms like Planarians, and even certain species of sharks.
The details of molecular intricacies will unfold with time, and hopefully, in the future, we will be able to exploit these characteristics and apply them for lifespan extension.
