In fact, well known ALS-related mutations, such as substitutions in the mostly disordered C-terminus of TDP-43 and the hexanucleotide expansion in C9orf72, were shown to impair phase separation of these proteins, suggesting their relevance in the onset of the pathological condition [86,87]. Additionally, altered proteostasis, which leads to the formation of aggregates in neuronal cells, is a hallmark of such conditions and was related to phase separation. Nonetheless, a complete understanding of how this aggregation influences the pathological outcome is still missing and requires further investigation to elucidate the exact relationship linking the fiber formation and the toxic effect
Further evidence for this mechanism of pathogenesis has come from studying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Work by several groups indicates that disease-related proteins, including FUS,, hnRNPA1, and TDP43, form liquid droplets before aggregating into pathological clumps. Genetic mutations found in patients with more aggressive forms of ALS or FTD increase the speed with which droplets of purified FUS, hnRNPA1, and TDP43 morph into plaque-like tangles. There is now a concerted effort to identify ways of preventing these proteins from undergoing pathological phase separation in cells, and even reversing the process after it has occurred.
THIS PAPER IS REALLY GOOD Physiological, pathological, and targetable membraneless organelles in neurons
The cell has various molecular chaperones that remodel misfolded proteins and contribute to proper maintenance of RNP-granule dynamics (
). Nuclear-import receptors also act as chaperones and dissolvases that reverse LLPS and aberrant phase separation of their RBP cargo (
,
,
,
). Small-molecule enhancers of these chaperones or de novo–designed chaperone proteins with enhanced disaggregase activity thus present promising approaches for targeting neurodegenerative diseases (
,
,
,
).
Short version: as cells age, their condensates drift from quick, squishy, reversible droplets toward slow, sticky, sometimes permanent gels. Longevity is, in part, keeping those droplets liquid, responsive, and under control so they don’t turn into biochemical hoarders.
What actually changes with age
- Material state “ages.” Condensates naturally “mature” from liquid to gel/solid if you stop actively maintaining them. Aging tilts the balance: solvent is lost, sticker–sticker bonds strengthen, and β-like fibrils nucleate inside, making dissolution harder and seeding pathology.
- Energy buffering drops. ATP isn’t just fuel; it’s a cellular hydrotrope that keeps many low-complexity proteins soluble. With age and stress, ATP availability and local ATP:protein ratios wobble, so droplets harden and aggregates linger.
- Disassembly machinery falters. Stress granules and P-bodies assemble fine, then overstay their welcome because chaperones, helicases, and autophagy aren’t as brisk. Older cells show altered SG/P-body composition and a bias toward amyloid-prone proteins. Net effect: chronic, half-dissolved granules that hijack RNA and translation.
- Genome organization shifts. Heterochromatin and nucleoli are condensates too. HP1-driven heterochromatin phase behavior and nucleolar size/dynamics change in senescence, scrambling transcriptional control and rRNA biogenesis.
- Neurons are especially touchy. Even without mutations, aging mispositions prion-like RNA-binding proteins (hello TDP-43) and destabilizes stress responses, priming neurodegeneration via condensate misregulation.
So what helps longevity?
Anything that keeps condensates liquid, selective, and reversible:
- Maintain ATP and proteostasis (exercise, sleep, CR-like signaling, fewer chronic stressors) so hydrotrope and chaperone capacity stay high. Rapamycin/spermidine-style autophagy helps clear stubborn assemblies. Evidence is indirect but consistent with how SG/P-body disassembly is energy and chaperone dependent.
- Keep chromatin architecture competent. HP1/heterochromatin integrity and nucleolar homeostasis correlate with healthier transcriptional noise, which echoes into better condensate control.
About melatonin and “reversing” phase separation
Your lens example is real biology, not fairy dust. In the eye, β/γ-crystallins undergo temperature/redox-tuned phase separation; with age, they phase-separate and then harden, giving you cataracts. The cited preprint argues melatonin both prevents crystallin LLPS and halts maturation into irreversible aggregates, via antioxidant chemistry and interactions that complement ATP’s hydrotropic effects. That’s plausible for lens proteins and fits broader hydrotrope/antioxidant logic, but it’s a preprint and tissue-specific. Scaling that claim to “melatonin globally fixes condensates across organs” is hypothesis, not consensus. Dose, kinetics, and target diversity matter.
For balance: cells already use small molecules to tune LLPS. ATP is the poster child; too little or too much changes droplet behavior. Pharmacologic condensate modulators exist, but many are blunt (think 1,6-hexanediol in vitro), and specificity in vivo is the hard part. Expect progress, but treat panacea rhetoric like a late-night infomercial.
Practical signals that condensate control is slipping
- Persistent stress granules after a stressor is gone
- Enlarged nucleoli and messy rRNA output in senescent cells
- Slow turnover of RNA-binding protein foci and chromatin mis-compartmentalizationThese are the cellular “traffic jams” that longevity regimens try to prevent or clear.
Bottom line
Healthy aging keeps condensates fluid, reversible, and on-task; unhealthy aging lets them gel, mis-select clients, and hijack gene control. Melatonin may be a useful lever in lens biology and possibly beyond, but the general, whole-body claim still needs the kind of evidence that survives peer review and dose-response reality. Until then, the boring fundamentals that preserve ATP, chaperones, and chromatin architecture are your safest condensate therapy. Try not to bankrupt your mitochondria attempting biochemical heroics.
You’re asking about three very different neighborhoods with very different physics. Short tour, no bathroom breaks:
Nucleus
- What’s separating: nucleolus, transcriptional hubs (Mediator/Pol II), nuclear speckles, heterochromatin droplets (HP1/Swi6).
- Aging drift: condensates get larger, slower, and stickier; heterochromatin loosens, nucleoli swell, and certain nuclear condensates (e.g., SGF29) accumulate and help lock in aging gene-expression programs. HP1/Swi6 condensation also sets nuclear mechanics, which shift with age. Net effect: noisier transcription and worse stress recovery.
Inner mitochondrial membrane (IMM)
- What’s separating: mostly lipid microdomains and protein–lipid patterning, not classic cytosolic droplets. Cardiolipin forms compositionally distinct regions that corral respiratory supercomplexes and shape cristae; its remodeling enables extreme protein crowding without the bilayer falling apart. OPA1 and the MICOS complex sculpt and gate crista junctions.
- Aging drift: cardiolipin composition oxidizes/remodels, OPA1/MICOS levels and organization falter, cristae lose density and connectivity. Translation: worse electron flow, leakier membranes, more ROS, less ATP, and poorer control over local microphase structure.
- Matrix side note: inside mitochondria, mt-nucleoids are bona fide phase-separated condensates built around TFAM; their material state affects genome maintenance and transcription. Evidence points to altered nucleoid dynamics with stress/aging.
Outer mitochondrial membrane (OMM)
-
What’s separating: signaling assemblies that behave like condensates or prion-like polymers on the membrane.
- Antiviral: MAVS forms self-propagating aggregates on the OMM to trigger interferon pathways. Great for killing viruses, less great if chronically mis-tuned.
- Mitophagy: upon damage, PINK1/Parkin drive ubiquitin-rich coats and recruit effectors; galectin-3 senses OMM rupture and helps organize clearance. These assemblies show condensate-like behavior at the membrane–cytosol interface.
- ER–mitochondria contacts (MAMs): lipid-ordered microdomains and tether complexes at ER–OMM junctions coordinate Ca²⁺, lipid flux, and metabolism; MAM architecture drifts with age and disease.
- Aging drift: weakened MAMs, slower mitophagy initiation, and chronic innate-immune signaling bias. That means damaged mitochondria linger, energy balance sags, and inflammatory tone rises.
Why this matters for longevity
- Keep nuclear condensates liquid and selective. Preserve heterochromatin organization and avoid nucleolar hypertrophy; when these go, transcriptional noise and senescence markers spike.
- Protect IMM lipid physics. Cardiolipin quality and OPA1/MICOS integrity preserve cristae and local “microphase” organization that power oxidative phosphorylation. When those slide, the whole ATP economy and redox control unravel.
- Keep OMM signaling assemblies timely, not chronic. Efficient mitophagy and sane MAVS dynamics stop the slide into inflammaging and mitochondrial junk accumulation.
Levers with plausible mechanistic links
- Mito fitness: endurance work and adequate sleep improve OPA1/MICOS function and cristae density in multiple models; less chronic ROS preserves cardiolipin.
- Proteostasis/clearance: autophagy inducers (rapamycin/spermidine class) and mitophagy competence keep OMM assemblies transient and clear stubborn granules.
- Chromatin health: interventions that restore heterochromatin organization reduce maladaptive nuclear condensates during senescence.
Bottom line: in the nucleus you’re managing protein/RNA condensates; at the IMM you’re guarding lipid–protein microphase architecture plus mt-nucleoids; at the OMM you’re policing signal-assemblies that decide life/death and immunity. Aging nudges all three toward larger, stickier, and slower. Longevity is keeping them fast, reversible, and discriminating, not letting them congeal into biochemical retirement homes.