Hallmark 10 of 12

Altered intercellular communication

The other hallmarks describe mostly what happens inside a cell. This one describes what happens between them. Hormones, immune messengers, nerve signals and vesicles that cells send each other change with age in recognisable patterns. This keeps ageing from being a local event: a disturbed tissue can act on distant organs through the bloodstream.

Scientific term: Altered intercellular communication
Group: Integrative consequences
Hallmarks of Aging: Described in 2013

The hallmarks of aging are a research framework, not a diagnostic tool. They describe processes that occur during ageing, but they do not prove causation and are not a basis for medical decisions.

What lies behind it

Communication runs through several channels. Endocrine via hormones in blood, paracrine via messengers to the immediate neighbourhood, neuronal via nerve pathways, and mechanical via the extracellular matrix, which stiffens with age and thereby alters signals itself. Extracellular vesicles that transport proteins and RNA between cells add to this.

At the hormonal level several axes are affected. The growth hormone axis, and with it IGF-1, flattens, a process termed somatopause. Sex hormones follow different courses: in women oestrogen production collapses within a few years at menopause, in men testosterone declines slowly and inconsistently. DHEA-S decreases continuously over decades, and the thyroid axis shifts moderately.

At the immune level a persistently slightly elevated background of inflammatory signals arises, fed among other things by senescent cells, bacterial components crossing over from the gut and leaked mitochondrial DNA. This background is listed as a hallmark in its own right and acts here as interference that overlays other messages.

The reach of these changes is practically significant. In animal models with joined circulations, the blood of an old animal influences the regeneration and cognition of a young one. That shows part of the ageing process is mediated by soluble factors in the circulation and is not fixed inside the cell.

How robust is the evidence

Moderate evidence

The mechanism is well documented; human data are largely observational.

That hormone levels change with age is well documented and uncontested. What is interesting and frequently misunderstood is the question of what correcting these changes achieves. Randomised trials do exist here, and their results are nuanced.

For menopausal hormone therapy the assessment has shifted over two decades. The Women’s Health Initiative initially led to a sharp fall in prescriptions. Later analyses by age and timing of initiation showed that benefit and risk depend heavily on how early after menopause treatment begins. For women with burdensome symptoms in the years after menopause the therapy is now considered defensible, while use solely to prevent age-related changes is not recommended.

For testosterone in men with low values and symptoms there are studies showing improvements in sexual function, mood and body composition. A large randomised trial of cardiovascular safety in men with hypogonadism and elevated cardiac risk found no increase in major cardiovascular events. A benefit for lifespan or prevention of age-related changes was not shown by this.

For growth hormone in healthy older people the balance is negative. A systematic review found small changes in body composition alongside a markedly increased rate of side effects such as joint pain, oedema and insulin resistance. For DHEA supplementation in healthy people, convincing evidence of benefit is lacking.

Findings in humans

IGF-1, DHEA-S and sex hormones follow documented but differently shaped curves with age.
Benefit and risk of menopausal hormone therapy depend strongly on age and on timing of initiation.
A large randomised trial of testosterone in hypogonadism with elevated cardiac risk found no increase in major cardiovascular events.
Growth hormone in healthy older people improved body composition only slightly, with a markedly increased side effect rate.
The extracellular matrix stiffens with age, which co-determines vascular stiffness and blood pressure behaviour.

What of this is measurable at YEARS

Partly, via adjacent markers

Of all twelve hallmarks this is the one routine diagnostics cover most broadly, because hormones and immune messengers are measurable in blood. Interpretation matters: what is measured are individual signalling values, not the quality of communication.

Hormone status: TSH, cortisol, DHEA-S, IGF-1, sex hormones

These values belong to basic endocrine diagnostics and are clinically informative when corresponding symptoms exist. Reference ranges are age-dependent, and a value in the lower normal range in someone past sixty is not a finding that requires treatment.

Inflammatory messengers: high-sensitivity CRP, interleukin-6

Capture the inflammatory background that overlays other signals. High-sensitivity CRP is established as a cardiovascular risk marker. Both values are non-specific and fluctuate considerably, for instance after infections or intense physical exertion.

Homocysteine and omega-3 index

Both touch the signalling environment, homocysteine via methylation capacity, the omega-3 index via cell membrane composition and the messengers derived from it. The link to clinical endpoints is weaker for homocysteine lowering through vitamins than was long assumed.

Context

A hormone value declining with age is not in itself an indication for treatment. Anti-ageing programmes that use growth hormone, testosterone or DHEA in the absence of symptoms in order to bring values to a youthful level are not supported by endpoint data. For growth hormone in healthy older people, the benefit-risk balance in the available evidence is negative.

Limits of this hallmark

The category is exceptionally broad. It contains hormones, immune messengers, nerve signals, mechanical properties of the matrix and vesicle transport. Such a catch-all category is hard to refute, and that is precisely a methodological problem: almost any ageing finding can somehow be classified as altered communication. For practical application it is therefore less sharp than the other hallmarks.

Inferring a sensible correction from an altered signal is the most common error in this field. That IGF-1 falls with age does not mean raising it helps; low IGF-1 is associated with lower cancer risk in some cohorts. That testosterone falls does not mean substitution helps in the absence of symptoms. The change could also be an adaptation.

Particular restraint is warranted in transferring conclusions from parabiosis experiments. Two animals with surgically joined circulations share not only blood but also organ function. No justification for plasma administration or blood transfusion for rejuvenation in humans can be derived from these experiments, and such offers operate outside controlled evidence.

Frequently asked questions

What is meant by altered intercellular communication?→

It means that signals between cells shift systematically with age. These signals run through several channels: hormones in blood, messengers to the immediate neighbourhood, nerve pathways, the extracellular matrix which stiffens with age, and vesicles transporting proteins and RNA. Typical changes are the flattening of the growth hormone axis, the decline of DHEA-S and sex hormones, and a persistently slightly elevated inflammatory background. The significance of this hallmark lies in its reach: a disturbed tissue can act on distant organs through the bloodstream. Ageing therefore does not remain a purely local event.

Should declining hormone levels be corrected with age?→

Not merely because they are falling. What matters is whether symptoms are present and whether trial data exist for the specific situation. For burdensome menopausal symptoms in the years after menopause, hormone therapy is now considered defensible, with benefit and risk depending strongly on age and timing of initiation. In men with low testosterone and matching symptoms, substitution can improve sexual function, mood and body composition. For use in the absence of symptoms, solely to bring values to a youthful level, there is no sound basis. For growth hormone in healthy older people the benefit-risk balance in available reviews is negative.

What should we make of plasma exchange or young blood?→

The idea comes from parabiosis experiments in which the circulations of an old and a young animal are surgically joined. There the regeneration of old muscle improved, and young animals in an old circulation showed poorer neurogenesis. These experiments have advanced research usefully but do not serve as justification for applications in humans. Two animals with joined circulations share not only blood but also organ function, liver and kidneys among them. Controlled trials with clinical endpoints on plasma administration or transfusions for rejuvenation do not exist. Offers of this kind operate outside demonstrated medicine and carry the usual transfusion risks.

Why is this hallmark considered less sharp than the others?→

Because it groups together very different things. Intercellular communication covers hormones, immune messengers, nerve signals, the mechanical properties of connective tissue and vesicle transport between cells. Such a broad category is hard to refute, since almost any ageing finding can somehow be read as altered communication. Therein lies the methodological weakness: a description that can absorb everything explains little. For practice it nevertheless remains useful, because it is a reminder that ageing happens not only inside cells but also between them and reaches distant organs through the bloodstream.

Sources

López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023;186(2):243–278.
Villeda SA, Luo J, Mosher KI, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011;477(7362):90–94.
Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353–1368.
Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular safety of testosterone-replacement therapy. New England Journal of Medicine. 2023;389(2):107–117.
Liu H, Bravata DM, Olkin I, et al. Systematic review: the safety and efficacy of growth hormone in the healthy elderly. Annals of Internal Medicine. 2007;146(2):104–115.

Related hallmarks

Hallmark 11 of 12