Essay

Live long and prosper

Short-circuiting the process of ageing

THE BIOLOGICAL BASIS of ageing can be traced to its beginning four billion years ago in a gene circuit in the first life forms that provided a survival advantage by turning off cellular reproduction while DNA was being repaired. One gene turns off reproduction; another makes a protein that turns off the first gene when it is safe to reproduce. When DNA breaks, the protein made by the second gene leaves to repair the DNA. As a result, the first gene is turned on to halt reproduction until that repair is complete.

The fossil record in our genes goes a long way to proving that every living thing that shares this planet with us still carries this ancient genetic survival circuit, in more or less the same basic form. It is there in every plant. It is there in every fungus. It is there in every animal.

It is there in all of us.

I propose the reason this gene circuit is conserved is that it is a rather simple and elegant solution to the challenges of a sometimes brutish and sometimes bounteous world that better ensures the survival of the organisms that carry it. It is, in essence, a primordial survival kit that diverts energy to the area of greatest need, fixing what exists in times when the stresses of the world are conspiring to wreak havoc on the genome, while permitting reproduction only when more favourable times prevail.

And it is so simple and so robust that not only did it ensure life’s continued existence on the planet, it ensured the Earth’s chemical survival circuit was passed on from parent to offspring, mutating and steadily improving, helping life continue for billions of years, no matter what the cosmos brought, and in many cases enabling individuals’ lives to continue for far longer than they actually need to.

The human body, though far from perfect and still evolving, carries an advanced version of the survival circuit that allows it to endure for decades past the age of reproduction. While it is interesting to speculate why our long lifespans first evolved – the need for grandparents to educate the tribe is one appealing theory – given the chaos that exists at the molecular scale it’s a wonder we survive thirty seconds, let alone make it to our reproductive years, let alone reach eighty more often than not.

But we do. Marvellously – miraculously – we do. But there is a trade-off. For this circuit within us, the descendant of a series of mutations in our most distant ancestors, is also the reason we age.

And yes, that definite singular article is correct. It is the reason.

 

IF YOU ARE taken aback by the notion that there is a singular cause of ageing, you are not alone. If you haven’t given any thought at all as to the way we age, that’s perfectly normal too. A lot of biologists haven’t given it much thought either. Even gerontologists, doctors who specialise in ageing, often don’t ask why we age – they simply seek to treat the consequences.

This isn’t a myopia specific to ageing. As recently as the late 1960s, the fight against cancer was a fight against its symptoms. There was no unified explanation for why cancer occurred, so doctors removed tumours as best they could and spent a lot of time telling patients to get their affairs in order. Cancer was ‘just the way it goes’, because that’s what we say when we can’t explain something.

Then, in the 1970s, genes were discovered that when mutated cause cancer. These so-called oncogenes shifted the entire paradigm of cancer research. Pharmaceutical developers now had targets to go after: BRAF, HER2, BCR-ABL. By devising chemicals that specifically block tumour-promoting proteins, we could finally begin to move away from using radiation and toxic chemotherapeutic agents to attack cancers at their genetic source, while leaving normal cells untouched. We certainly haven’t cured all types of cancer in the decades since, but we no longer believe it’s impossible.

In May 2010, a group of nineteen scientists meeting under the auspices of the Royal Society in London moved towards a provocative consensus: that ageing is not an inevitable part of life, but rather a ‘disease process with a broad spectrum of pathological consequences’. In this way of framing the issue, cancer, heart disease, Alzheimer’s and other conditions we commonly associate with getting old are not necessarily diseases themselves but symptoms of something greater.

That greater phenomenon is ageing itself; it is the disease that disables 93 per cent of people over the age of fifty. On 18 June 2018, when the World Health Organization (WHO) released the eleventh edition of the International Classification of Diseases (ICD-11), it included a new disease code:

MG2A Old Age

• old age without mention of psychosis

• senescence without mention of psychosis

• senile debility

Every country in the world is encouraged to start reporting using ICD-11 on 1 January 2022. Which means it is now possible to be diagnosed with a condition called ‘old age’. Countries across the world will have to report back to the WHO on who dies from ageing as a condition.

 

IF WE ARE to make real progress in the effort to alleviate the suffering that comes with ageing, what is needed is a unified explanation for why we age, not just at the evolutionary level but at the molecular level.

About a decade ago, the ideas of leading scientists in the ageing field began to coalesce around a model that suggested there were eight or nine hallmarks of ageing: genomic instability; attrition of protective chromosomal endcaps called telomeres; alterations of the epigenome; loss of healthy protein maintenance; deregulated nutrient sensing; mitochondrial dysfunction; accumulation of senescent zombie-like cells; exhaustion of stem cells; the production of inflammatory molecules. There is little doubt that the list of hallmarks, though incomplete, comprises the beginnings of a rather strong tactical manual for living longer and healthier lives. Interventions aimed at slowing any one of these hallmarks may add a few years of wellness to our lives. If we can address all of them, the reward could be vastly increased average lifespans.

Finding a universal explanation for anything doesn’t occur overnight. Any theory that seeks to explain ageing must not just stand up to scientific scrutiny but provide a rational explanation for every one of the pillars of ageing. A universal hypothesis that seems to provide a reason for cellular senescence but not stem-cell exhaustion would explain neither.

Yet I believe that such an answer exists – a cause of ageing that exists upstream of all the hallmarks. A singular reason why we age.

Ageing, quite simply, is a loss of information.

 

THERE ARE TWO types of information in biology and they are encoded entirely differently. The first type of information is digital, based on a finite set of possible values – in this case, not zeroes and ones like computers, but the four chemicals that encode information in DNA, known as A, T, C and G. Because DNA is digital, it is a reliable way to store and copy information. It can be copied again and again with tremendous accuracy – in principle no different to digital information stored in computer memory or on a DVD.

DNA is also robust – this ‘molecule of life’ can survive for hours in boiling water and be recovered from Neanderthal remains at least 40,000 years old. The advantages of digital storage explain why chains of nucleic acids have remained the go-to biological storage molecule for the past four billion years.

The other type of information in the body is analogue. We don’t hear as much about analogue information in the body – in part because it’s newer to science and in part because it’s rarely described in terms of information. But that was how it was first described when geneticists noticed strange nongenetic effects in plants they were breeding. Today, analogue information is more commonly referred to as the epigenome, meaning traits that are heritable but aren’t transmitted by genetic means.

In simple species, epigenetic information storage and transfer is important for survival. For complex life – from slime moulds, jellyfish and fruit flies to mammals like us – it’s essential. Epigenetic information is what orchestrates the assembly of a human newborn made up of twenty-six billion cells from a single fertilised egg and what allows the genetically identical cells in our bodies to assume thousands of different modalities.

If the genome were a computer, the epigenome would be the software. It instructs the newly divided cells on what type of cells they should be and what they should remain, sometimes for decades, as in the case of individual brain neurons and certain immune cells. That’s why a neuron doesn’t one day behave like a skin cell, and a dividing kidney cell doesn’t give rise to two liver cells. Without epigenetic information, cells would quickly lose their identity, and new cells would lose their identity too. If they did, tissues and organs would eventually become less and less functional until they failed.

In the warm ponds of primordial Earth, a digital chemical system was the best way to store long-term genetic data. But information storage was also needed to record and respond to environmental conditions, and this was best stored in analogue format. Analogue data are superior for this job because they can be changed back and forth with relative ease whenever the environment within or outside the cell demands it, and they can store an almost unlimited number of possible values, even in response to conditions they haven’t encountered before.

The unlimited number of possible values is why many audiophiles still prefer the rich sounds of analogue storage systems. But these have a major disadvantage: analogue information degrades over time – falling victim to the conspiring forces of magnetic fields, gravity, cosmic rays and oxygen. Worse still, information is lost as it’s copied.

But don’t be disheartened by my claim that we are the biological equivalent of an old DVD player: that is actually good news. Although as anyone who’s tried to play or restore content from a DVD with a broken edge will know, what is gone is gone. But we can usually recover information from a scratched DVD. And if I am right, the same kind of process is what it will take to reverse ageing.

As cloning beautifully proves, our cells retain their youthful digital information even when we are old. To become young again, we just need to find some polish to remove the scratches.

This, I believe, is possible.

 

THE INFORMATION THEORY of ageing starts with that primordial survival circuit. Over time, the circuit has evolved. Mammals, for instance, don’t have just a couple of genes that create this circuit; there are more than two dozen of them within our genome. Most of my colleagues call these ‘longevity genes’ because they have demonstrated the ability to extend both average and maximum lifespans in many organisms. But these genes also make life healthier, which is why they can also be thought of as ‘vitality genes’.

Together, they form a surveillance network within our bodies, communicating with one another between cells and between organs by releasing proteins and chemicals into the bloodstream, monitoring and responding to what we eat, how much we exercise and what time of day it is. They tell us to hunker down when the going gets tough, and they tell us to grow fast and reproduce fast when the going gets easier.

Now that we know these genes are there and what many of them do, scientific discovery has given us an opportunity to explore and exploit them; to imagine their potential; to push them to work for us in different ways. Using molecules both natural and novel, using technologies both simple and complex, using wisdom both new and old, we can read them, turn them up and down, and even change them altogether.

The longevity genes I work on are called ‘sirtuins’ – there are seven in mammals, and they are made by almost every cell in the body. These critical epigenetic regulators sit at the very top of cellular control systems, controlling our reproduction and our DNA repair. After a few billion years of advancement, they have evolved to control our health, our fitness and our very survival. They have also evolved to require a molecule called nicotinamide adenine dinucleotide, or NAD. The loss of NAD as we age, and the resulting decline in sirtuin activity, is thought to be the primary reason our bodies develop diseases when we are old but not when we are young.

Trading reproduction for repair, the sirtuins order our bodies to ‘buckle down’ in times of stress and protect us against the major diseases of ageing: diabetes and heart disease, Alzheimer’s disease and osteoporosis – even cancer. They mute the chronic, overactive inflammation that drives diseases such as atherosclerosis, metabolic disorders, ulcerative colitis, arthritis and asthma. They prevent cell death and boost mitochondria, the power packs of cells. They go to battle with muscle wasting, osteoporosis and macular degeneration. In studies on mice, activating the sirtuins can improve DNA repair, boost memory, increase exercise endurance and help the mice stay thin, regardless of what they eat.

Sirtuins aren’t the only longevity genes. Two other very well-studied sets of genes perform similar roles, which also have been proven to be manipulable in ways that can offer longer and healthier lives. Scientists have found the longevity proteins that sense amino acid deprivation known as TOR in every organism in which they’ve looked for it. When all is well and fine, TOR is a master driver of cell growth. When it is inhibited, it forces cells to hunker down, dividing less and re-using old cellular components to maintain energy and extend survival – like going to the junkyard to find parts with which to fix up an old car rather than buying a new one. The other pathway is a metabolic-control enzyme known as AMPK, which evolved to respond to low energy levels. It has also been highly conserved among species, and we have learnt a lot about how to control it. These defence systems are all activated in response to biological stress.

Clearly some stresses are simply too great to overcome – step on a snail and its days are over. But here’s the important point: there are plenty of stressors that will activate longevity genes without damaging the cell, including certain types of exercise, intermittent fasting, low-protein diets and exposure to hot and cold temperatures. That’s called hormesis, and it’s generally good for organisms, especially when it can be induced without causing any lasting damage. When hormesis happens all is better than well because the little bit of stress that occurs when the genes are activated prompts the rest of the system to conserve, to survive a little longer. That’s the start of longevity.

Our ability to control all of these genetic pathways will fundamentally transform medicine and the shape of our everyday lives. Indeed, it will change the way we define our species.

This is an edited extract from Lifespan: Why We Age – and Why We Don’t Have To by David Sinclair and Matthew D LaPlante (Thorsons, 2019).

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