Ageing: En route to determining our future

A baby holding an old grandma's hand

Understanding ageing better may help provide a healthier life to the older population. Image credit: Rod Long, via Unsplash.

Nothing in biology makes sense except in the light of evolution’, stated the geneticist Theodosius Dobzhansky. Although almost a century has passed since this was first said, the natural world remains as much a mystery now as it did then. As we get older, we lose biological integrity, leading to a progressive loss of physiological function and vulnerability to death. Therefore, despite the fact that natural selection favours features that advance species survival, ageing seems an elusive property of life—a longstanding enigma hardly subjected to natural selection.

Identifying the cause of mortality and discovering its Achilles’ heel has attracted great curiosity throughout history. Interestingly, recent findings show that humans are living longer. Scientists are looking at the molecular mechanisms behind human longevity to identify ways of increasing healthy life expectancy. However, geroscience, the field studying the biology of ageing, has attracted great controversy and criticism, particularly for the ethical considerations of studying human longevity. At older ages, many people develop age-related diseases.

This often reinforces a public attitude that erroneously equates ageing with frailty and appraises the older population as vulnerable and dependent. Ageism, defined as the discrimination of an individual based on their age, creates harmful narratives about older individuals. Age biases isolate the older population and discourages them from engaging in social activities. To improve their quality of life and counter those stereotypes, reflecting on the real-life consequences they face and identifying ways to help them live more healthily is essential.

What is ageing?

Ageing is the process of getting older, characterised by the gradual decline of physiological, cellular, and molecular function, damage accumulation, and higher mortality rates. This results from the interactions of the individual body capacity (defined as the “internal” or “intrinsic” system), that deteriorates progressively, and the environment (defined as the “external” or “extrinsic” system). We classify age into different types: “chronological age”, defined as the number of years alive, and “biological age”, based on the health status of an individual. Ageing is a complex, unstructured, and natural process that varies from one person to another. It is not a disease itself but is often accompanied by a collection of age-related diseases. These include type II diabetes, neurodegenerative, cardiovascular, orthopaedic and musculoskeletal diseases, cataracts, and cancer.

The evolution of ageing—an enduring puzzle

Dating back to ancient times, the first theories of ageing developed as early as the fourth century BCE. In ancient Greece, Hippocrates described ageing as the result of the progressive loss of innate heat, the depletion of which leads to death. Plato and Aristotle further elaborated on this theory, considering the extrinsic stimuli (such as nutrition or environmental niche) influencing the ageing process. Galen described the process of getting old as natural and lifelong, indicating that death derives from the ‘body deteriorating of itself’. Interestingly, he recognised the diversity of this process among individuals and proposed that exercise and diet could postpone it.

The traditional theories mentioned above approach the changes observed with age in a physiological manner. More recent theories focus on molecular changes, investigating the underlying mechanisms involved in the ageing process. Whether the nature of ageing is a programmed or non-programmed process has been a long-lasting subject of debate. For instance, the genetic profile and lifespan seem to be conserved across species (meaning they have changed little throughout evolutionary history), supporting the idea of a programmed mechanism. However, the inter-species variability in lifespan and healthspan indicates that a controlled mechanism leading to ageing and mortality may not be feasible. If such a programme existed, individuals would be expected to show signs of ageing accompanied by molecular changes, leading to age-related diseases in a controlled manner. They would thus possess the effects of programmed ageing at the same time and with the same severity, which is not the case. Besides, ageing is not universal, and species, such as hydra, do not present any signs of ageing.

Ageing seems an elusive property of life—a longstanding enigma hardly subjected to natural selection.’

Searching for specific “genes for ageing” would be intriguing. Studies have shown that specific genes (i.e., insulin growth factor 1, IGF-1) can change with age, resulting in age-related impairments. IGF-1 is responsible for nutrient signalling and progressively declines with age. Scientists have found that maintaining levels of IGF-1 correlates with an extended lifespan. Nonetheless, no research has yet identified a specific set of genes that induce the ageing process. Besides, it would be against natural selection, and therefore, evolutionarily unstable to possess a gene responsible for ageing without having individuals with mutations that would disrupt death. Mutations are a critical part of evolution. If a mutation that would lead to individual immortality existed, it would benefit that individual’s fitness. Thus, natural selection would favour this advantageous mutation, and through reproduction, it would spread the fitness advantage across our species. Since there is no evidence of immortality across species, we cannot hypothesise the existence of genes that lead to ageing.

From a genetics point of view, Medawar (1952) and Williams (1957) proposed two closely-linked theories: the selection shadow (or mutation accumulation theory), and age pleiotropy. Genes are located within cells and collectively make up an organism’s genome. According to the mutation accumulation theory, genes that confer deleterious effects later in life are distributed throughout the genome. Thus, natural selection is unable to eliminate these since the individuals have already reproduced by the time those harmful effects accumulate. For instance, people possessing a mutation at the huntingtin gene, causing Huntington’s disease, do not present any symptoms until later in life.

Similarly, the age pleiotropy theory suggests that genes with beneficial effects early in life are favoured by natural selection, even if possession of the same gene becomes detrimental later. For example, cellular senescence, the irreversible cellular pause, is essential during normal mammalian development, promoting wound healing and protecting against cancer. With advancing age, increased levels of cellular senescence confer detrimental effects on the individual, contributing to the development of chronic diseases. As fewer individuals survive to, and reproduce at, greater ages, natural selection has less opportunity to act on any genes which have an effect in later life. With weaker selection against them, they are often passed on to later generations despite their adverse effects.

Although human longevity appears to have a genetic component, non-genetic factors like nutrition and lifestyle also have a significant role. We must therefore consider both intrinsic between-individual variation and extrinsic forces to understand the multiplicity of mechanisms in longevity.

The hallmarks of ageing

Discovering certain hallmarks of ageing has fuelled the study of longevity. These are biological changes that occur in organisms as they age and describe nine mechanisms that are characteristic of ageing and age-related diseases. These hallmarks, outlined by research organisations Sense About Science and UK SPINE, include functional changes at the molecular and cellular levels. These changes decline the overall physiological homeostasis of the individual and lessen their ability to perform daily physical and cognitive activities.

The hallmarks of ageing. Adapted from UK SPINE, Making sense of ageing researchSense about Science.

The new era: Why is ageing research essential?

According to the World Health Organization (WHO), the global population of people over 60 is expected to double by 2050, increasing from 1 to 2.1 billion. Currently, there are more people aged over sixty than there are children under five years old. This remarkable increase in lifespan has not been matched by the (necessary) increase in ‘healthspan’, or the number of healthy years living disease-free. The world’s population, therefore, lives longer but not more healthily.

Age is the greatest risk factor for developing various long-term medical conditions. The final years of life are often characterised by multiple severe chronic diseases. Using multiple medications simultaneously is common among older people, who have often been prescribed many drugs for different diseases (known as polypharmacy). Their immune system is also compromised, making them more vulnerable to infections, such as COVID-19, and reducing the efficacy of their vaccine responses.

Ageing research is essential for developing therapeutic interventions that will lessen the detrimental effects of ageing for the individual, their families, and the healthcare system. We now know that many age-related diseases have common underlying biological causes or share molecular and cellular changes. Therefore, ageing researchers take a holistic approach by looking at the whole body and investigating different ways of addressing the onset of multiple age-related diseases simultaneously. This will be achieved by discovering interventions that will possibly target multimorbidities with a single drug and help live a long and healthy life.

Increased lifespan, or the number of years a person is alive, does not correspond with increased healthspan, or a number of years a person is disease-free. Left: The global increase in human lifespan. Derived from Oeppen & Vaupel, 2002. Right: Number of conditions accumulating with increasing age. Derived from Jacopo Lenzi et al., 2016.

Is the end-goal lifespan expansion or just a better quality of life?

More than 46% of the elderly population globally (over 250 million people aged over 60) struggle with debilitating disabilities. However, illnesses cannot be entirely prevented, and immortality is not the end goal of ageing studies. Contrariwise, investigating ageing implies identifying interventions that will expand the years living in a healthy condition and postpone the molecular age-related changes that lead to diseases. Scientists aim to improve the lives of the older population, accompanied by a slight increase in their lifespan. UK SPINE indicates that the ultimate goal of ageing studies is to reduce the difficulties associated with age-related diseases. A better understanding of ageing biology will better equip the healthcare systems to support individuals with personalised approaches as they age and ultimately reduce healthcare inequalities.

Ageing is the future. Heraclitus said, “Ἦθος ἀνθρώπῳ δαίμων” (Ithos anthropo daimon), or ‘a man’s character is his fate’, which fits the idea that the way the elderly population is treated is the way we will all be treated one day. Each researcher and medical professional has different inspirations that drive their motivation for their work. Regardless, these generally derive from the same noble objective: to make a positive impact on peoples’ lives. The advantages of the knowledge derived from  ageing research will help us improve individual lives and create a better society. Expanding our understanding of longevity, and investigating the underlying causes of ageing diseases, will help provide a healthier life to the older population and identify the origin of diseases threatening us all. Targeting ageing will also give us an idea of the current healthcare issues and inequalities in the medical sector, allowing us to make the appropriate changes to terminate them. Ultimately, the results of ageing research will enable us to change our perspective about getting old and to fight for a better future for everyone, creating a world where we can all grow together.

Aiming to improve healthspan. Derived from UK SPINE, Making sense of ageing researchSense about Science.