Epigenetic clocks — a type of biomarker that estimates biological age by analysing DNA methylation patterns — can estimate accelerated biological ageing in cells, tissues or organs.³ This is a means of identifying problematic biochemical trends before diseases manifest. More recent advances integrate statistics from multiple epigenetic biomarkers to predict mortality.⁴

Validating these biomarkers so that they are reliable and consistent is the key to making biological age a useful tool. Because biomarkers are statistical tools whose power lies in the amount of data that they can draw on, the more population data that is available against which to benchmark individuals, the more accurately the tools will be able to identify patterns and make predictions. One promising model, the Global Neurodegeneration Proteomics Consortium,⁵ combines the data of 40,000 individuals and solves data-privacy issues via federation of access and cloud analysis. Mining this and future large datasets, including the UK Biobank, will refine biomarkers of ageing.

Epigenetic reprogramming to turn the body’s somatic cells into pluripotent cells has been investigated for decades. This is mediated by proteins called transcription factors and has been shown to have rejuvenating effects in preclinical trials.⁶ However, the mechanism (which uses four transcription factors — known collectively as OSKM — that are delivered by viral payload) carries an inherent risk of cancer.⁷ Safety will be key to human translation, meaning that potentially cancer-causing transcription factors will need to be replaced by small molecule drugs or other alternatives. Early work identifying safer transcription factors, including HNF4 alpha, which can rejuvenate the liver, is under way. The epigenome may also be targeted more indirectly, including by the SIRT6 activator fucoidan or forskolin.⁸

Instead of in vivo modification, ex vivo interventions could be undertaken to reprogram aged stem cells before reintroducing them to the body. This would allow more control of the process. This approach is a focus of current research for reprogramming transplant organs, such as kidneys and hearts, which are epigenetically rejuvenated before being introduced into a recipient.⁹

Of particular interest for geroscience are transposons: repeating, self-replicating DNA sequences that can alter their location in the genome.¹⁰ Also known as “jumping genes”, they make up about half of the genome. Their activity — which increases with an organism’s age — can alter chromosome structure, destabilise the genome, trigger immune response and inflammation,¹¹ and create other conditions that have been tied to poor health outcomes in old age.¹² Turning them off seems to have broad health benefits, as revealed in HIV antiretroviral therapies that turn off the “LINE” transposons (among the most prevalent repeating sequences, and major contributors to human genetic variation).¹³ This reverses the age-accelerating effects of HIV with no health trade-offs.¹⁴ Doing so holds promise for other diseases associated with LINE-1, such as rheumatoid arthritis¹⁵ and lupus.¹⁶

However, manipulating the dark genome will be more complex than simply finding a general-purpose “off” switch. Preclinical trials are beginning to show that, under certain conditions, some parts of the dark genome might have beneficial effects. Also, a better understanding of how non-coding elements interact with coding elements may yield a rich new source of new biomarkers and potentially even therapies. Our understanding of the dark genome has been hampered by technological limitations of DNA and RNA sequencing requiring fragmentation followed by aligning to reference sequences to forecast the underlying sequence. New technologies, including nanopore, which allows direct reading of long sequences of DNA and RNA, are advancing our understanding of the dark genome,¹⁷ but more research into these intricate relationships and how to balance the trade-offs is needed. Excitingly, the dark genome appears to be responsive to rejuvenation, so a better understanding of rejuvenation may also shed light on it.

What’s more, the interplay between two or more behavioural or environmental interventions can amplify the efficacy of each, as suggested by mouse trials in which calorie restriction’s moderate benefits for lifespan and healthspan were multiplied several times over by combination with circadian timing patterns of eating.¹⁹ However, how single or multiple behaviours are transduced into cellular changes is an area of open research.

While that research continues, efforts are under way to find ways to boost circadian rhythms associated with not just sleep/wake cycles but also body temperature, blood pressure and so on. Their fluctuations are controlled by time-keeping proteins encoded in master clock genes, and drugs that enhance the master clocks could make us healthier. This should have beneficial effects, since these clocks regulate the genes in all 12 hallmarks of ageing pathways,²⁰ and seem to regulate sleep, metabolism and neurodegeneration. In mice, boosting clock gene expression yielded a 15 per cent increase in lifespan.

Finding and measuring biomarkers that link lifestyle choices with clocks will open the possibility of lifestyle mimetics, small-molecule drugs that could manipulate the same pathways and slow ageing before disease manifests.

We may already be administering such drugs. The immunosuppressant rapamycin, whose signalling is increasingly understood to influence longevity and ageing, and the metabolic drug metformin have been in clinical trials for their suspected ability to mimic lifestyle benefits. More recent investigations have studied drugs that target sirtuins. Stimulation of sirtuin 6 (SIRT6) has extended lifespan in mice, rejuvenated the epigenome and silenced transposable elements. Activating SIRT6 or similar epigenetic regulators with small molecules or natural compounds will provide safe ways to improve healthspan.²¹ Fucoidan, a natural SIRT6-activating compound, is under test in a clinical trial for its ability to slow the biomarkers of ageing in humans.