By Temea Turjaka - Biochemistry Student @ Christ Church College, Oxford
Today, humans are living longer - and ageing for a greater proportion of that time - than ever before. We can define ageing as the progressive loss of bodily function over time that increases the probability of death. However, an unforeseen consequence of this process is that we are spending an ever-increasing portion of our lives being sick and in need of care. Thus, scientists are shifting the attention of the medical community from increasing lifespans to optimising healthspans (the part of our lives where we are free of disease). The most effective way to treat disease is to prevent it, so if we can banish ageing, we can reduce the impact of many diseases.
The Double-Agent Theory of Ageing and Disease
Old age is not a function of time, but a function of oxidative stress, which tends to rise over time. Thus, if we can prevent oxidative stress, we should be able to prevent degenerative diseases. You might think that antioxidants are the solution to this, but dietary antioxidants are far from a panacea. They may even be counter-productive, as they suppress the genetic response to oxidative stress that is produced by haem oxygenase and metallothionein proteins.
The name of the double-agent theory comes from the duplicitous role of oxidative stress, because it confers resistance to disease in youth via cell-signalling pathways in fighting infection, and vulnerability to disease at old age. For example, oxidative stress activates transcription factors like NF-kb, which coordinates the response of promoting inflammation to fight infection. In old cells, this promotion of inflammation becomes chronic and persistent, leading to diseases such as arthritis, heart disease, and cancer.
Telomeres- the end replication problem
Telomeres are regions at the very end of eukaryotic chromosomes, with a single DNA sequence repeated. Telomeres act as caps that protect the internal regions of the chromosomes and are worn down a small amount in each round of DNA replication. Telomere length shortens with age.
During DNA replication, one of the two new strands of DNA at a replication fork is made continuously (leading strand). The other strand is produced in many small pieces called Okazaki fragments, each of which begins with its own RNA primer (lagging strand). The primers of the Okazaki fragments can be replaced with DNA and the fragments connected to form an unbroken strand. However, when the replication fork reaches the end of the chromosome, a short stretch of DNA does not get covered by an Okazaki fragment. The primer of the last Okazaki fragment that does get made can't be replaced with DNA like other primers.
Part of the DNA in the telomeres goes uncopied in each round of replication, leaving a single-stranded overhang. Over multiple rounds of cell division, the chromosome will get shorter and shorter.
Eventually, telomeres get too short to do their job and become senescent cells. The number of senescent cells goes up with age. They stop dividing and cause inflammation and tissue damage via the ‘senescence associated secretory phenotype’. They also change gene expression so genes that should be tightly regulated are always switched on, and are resistant to cell death. They are much like ‘zombie’ cells, able to make neighbouring cells senescent too.
Senolytics - part of a class of small molecules under research to determine if they can selectively induce death of senescent cells and improve health in humans - are currently undergoing clinical trials. The mTOR signalling pathway has been shown to be permanently switched on in old, laboratory-grown cells. This indicates that there is a biochemical switch that should be regulated, but in old cells is permanently turned on, like an overflowing tap. ‘Turning off the tap’ through mTOR inhibition reverses features of senescence.
Furthermore, the drugs rapamycin and AZT have been shown to delay the onset of senescence, or even reverse it, by suppressing the secretory phenotype. These drugs contribute to rearranging the cytoskeleton to allow cells to move better. Ongoing clinical trials show rejuvenation of human skin cells, support in the elderly immune system, and treatment of respiratory infections. Other treatments or cures for ageing being studied include NAD and stem cell treatment.
Further Reading:
‘OXYGEN’ by Nick Lane, chapter 14
Article on telomeres and telomerase available at: https://www.khanacademy.org/science/biology/dna-as-the-genetic-material/dna-replication/a/telomeres-telomerase
Research paper on ‘Senolytics in idiopathic pulmonary fibrosis’ available at: https://www.sciencedirect.com/science/article/pii/S2352396418306297
Understanding the Odd Science of Ageing https://www.cell.com/fulltext/S0092-8674(05)00101-7
Research paper on ‘mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases’ available at: https://pubmed.ncbi.nlm.nih.gov/30096787/