Vecchiaia ed alimentazione adatta

DIETA, EVOLUZIONE e VECCHIAIA  –  DIET, evolution and Aging (English)
E’ INDISPENSABILE per stare sempre BENE e’ l’assunzione quotidiana, per certi periodi,
di acqua Basica a pH min. di 7,35 > 11 (almeno 1,5 lt)
Le bevande troppo saline e/o le bevande industriali, non vanno bevute giornalmente e/o spesso,
anche e per le loro forti acidita’, in quanto influiscono sull’alterazione dei giusti valori di pH dell’acqua del corpo.
L’acidosi e’ la base fisiologica del Cancro –  Il Conflitto Spirituale Irrisolto, ne e’ la Causa primaria

Quindi se volete fare un Test di Bioelettronica (test di controllo del livello di Salute_benessere)….
– scrivete QUI: info@mednat.news

La natura biologica della senescenza (dal latino senectus, e’ sinonimo di invecchiamento).
Essa e’ il processo di invecchiamento di un organismo, accompagnato da fenomeni involutivi di tipo fisiologico e funzionale: la s. delle cellule, infatti l’acidosi e’ la madre delle malattie e base per l’invecchiamento precoce.
vedi: Acidosi metabolica + Acidosi + Acidosi nel cancro + Iperacidosi + Acidosi organiche

Continua QUI: Biofotoni + Bioelettronica + Cellule

Il concetto di vecchiaia nella storia della medicina
Nel cammino ultra millenario dell’umanità la maledizione della vecchiaia non era stata prevista né da un dio crudele, né da una natura malvagia; essa è semplicemente un accidente provocato dalla nascita della socialità nella nostra specie.
Difendere i deboli, procacciare il cibo a chi non è più in grado di procurarselo, saranno pure comportamenti degni di lode, ma, uniti ai continui progressi della medicina, hanno partorito una mostruosità.
L’uomo delle caverne, al pari di tutti gli animali, non era destinato ala vecchiaia, non l’avrebbe mai conosciuta, se i suoi simili non l’avessero aiutato quando il suo percorso terreno era biologicamente concluso.
Allungandosi la vita nessuno uomo può sfuggire alla vecchiaia, una condizione ineluttabile ed irreversibile. La longevità dell’uomo è superiore a quella di tutti i mammiferi, ma inferiore a quella di altri animali, dalla tartaruga all’elefante. In tutte le specie le femmine vivono più a lungo, nel mondo civilizzato le donne sette anni più degli uomini.

La medicina si è sempre interrogata sulle cause che portano l’uomo al disfacimento fisico e fino ad oggi non è stata in grado di fornire una risposta soddisfacente e definitiva.
Presso i popoli antichi il sapere medico si confondeva con la metafisica ed alla speculazione filosofica. Soltanto con  Ippocrate cominciò a divenire una scienza ed un’arte. Il sommo pensatore riteneva che si diventasse vecchi a cinquantasei anni ed osservò e descrisse molte manifestazioni dell’ultima età dell’uomo. Paragonava le tappe della vita allo scorrere delle stagioni, dalla primavera all’inverno, similitudine che ebbe successo per secoli.

Aristotele dava molto risalto alla speculazione e poco all’esperienza. Riteneva che la vita fosse legata al calore interno, il quale, quando scemava, dava luogo a senescenza.
Nel II secolo Galeno, nell’operare una sintesi delle conoscenze mediche precedenti, collocava la vecchiaia a metà tra la malattia e la salute. Cercò inoltre di conciliare la teoria degli umori con quella del calore interno e credeva che il corpo fosse il contenitore dell’anima. Le sue conclusioni furono accettate acriticamente a lungo non solo dai padri della Chiesa, ma anche dagli Ebrei e dal mondo islamico.
Gli Scolastici paragonavano la vita ad una fiamma che diveniva lentamente sempre più fioca, un’immagine mistica che perdurò per tutto il medioevo.

La Scuola di Salerno, culla della medicina occidentale, elargiva consigli per conservare la salute e vivere a lungo, insegnamento non dissimile da quello impartito dalla Scuola di Montpellier, anche essa prodiga di regimi salutari.
Nel Quattrocento vede la luce il primo libro dedicato alle malattie della vecchiaia ”Gerontocomia”, ma un vero passo avanti nelle conoscenze si avrà solamente con le scoperte dell’anatomia grazie a Leonardo da Vinci, che seziona circa trenta cadaveri, molti di vecchi, dei quali ci descrive con precisione gli intestini e le arterie; purtroppo le sue osservazioni  furono note solo dopo molto tempo.

L’Umanesimo cerca disperatamente di contrastare la metafisica, che ancora impregna e rallenta i progressi della scienza, la quale si avvale delle scoperete anatomiche di Vesalio, mentre Paracelso riteneva la vecchiaia il prodotto di un’autointossicazione.
Per secoli continuavano ad avere seguaci le teorie meccanicistiche dell’antichità, di Democrito e di Epicuro, basate sulla concezione del corpo umano paragonato ad una macchina soggetta all’usura.
Il Morgagni, grande anatomo patologo, grazie ai risultati di innumerevoli autopsie riscontrò uno stretto rapporto tra sintomo e danno organico. Tra i suoi scritti vi è un capitolo dedicato alla vecchiaia.

Nell’Ottocento nella popolazione europea comincia ad aumentare il numero degli anziani e mentre la Scuola di Montpellier continua a credere nel vitalismo, in Francia, presso l’ospedale Salpetriere viene a crearsi il primo ospizio forte di circa tremila vecchi su di un totale di ottomila ricoverati. Fu così sempre più agevole osservare patologie legate alla senescenza e in quegli anni il celebre Charcot, le cui lezioni tanto influenzarono Sigmund Freud, tenne numerose conferenze sulla vecchiaia, le quali, una volta pubblicate, ebbero notevole risonanza.

Su finire del secolo si profilano le prime ipotesi sulla genesi della vecchiaia: Brown-Sequard credeva che fosse legata ad un’involuzione delle ghiandole sessuali ed a settantadue anni, speranzoso, si iniettò estratti di testicoli di cavia e di cane con risultati modesti e transitori; Voronoff pensò di trapiantare agli anziani ghiandole di scimmia, ma senza esiti favorevoli ed inconcludenti furono anche tutti i tentativi di altri scienziati con sieri a base di estratti ormonali.
Il Novecento si apre con l’affermazione di Cazalis: ”L’uomo ha l’età delle sue arterie”, un assioma ancora ritenuto valido, anche se come effetto e non come causa ed identificò nell’arteriosclerosi il fattore scatenante del decadimento fisico.

Il padre della moderna geriatria è comunemente ritenuto l’americano Nasher,  che passò una vita a studiare il problema, a cui dedicò una specifica branca della medicina. Nello stesso tempo si sviluppò una scienza parallela detta gerontologia, la quale, più che i processi patologici, cercò di indagare i processi ancora sconosciuti della senescenza.
Mentre ancora famosi studiosi come Carrel riproponevano l’ipotesi che la vecchiaia fosse dovuta ad un’intossicazione provocata dal metabolismo cellulare, negli Stati Uniti venivano pubblicati numerosi trattati dedicati all’argomento.

Attualmente la medicina non pretende di identificare una causa dell’invecchiamento, considerata una fase della vita alla pari della nascita, della crescita, della riproduzione e della morte. Si tratta di un processo comune a tutti i viventi anche se solo gli uomini e gli animali in cattività sono condannati a sopportarlo.
Se osserviamo infatti gli animali in libertà, senza dimenticare che anche noi lo siamo, ci accorgiamo che non conoscono né vecchiaia, né lunghe malattie ed invece, con il nostro incauto comportamento, abbiamo condannato a queste maledizioni anche gli animali domestici.
La natura nella sua infinita saggezza, o Dio se vi fa più piacere, non aveva previsto per l’uomo che si potessero superare i trenta, quaranta anni: la menopausa per le donne, la calvizie per gli uomini, la presbiopia per entrambi sono aberrazioni non programmate.

L’uomo viveva nel vigore della giovinezza e moriva nel pieno delle proprie forze, non conosceva l’umiliazione del degrado fisico e la morte per consunzione. Poi la civiltà, la prosperità e la scienza hanno aggiunto anni alla vita senza aggiungere vita agli anni, dando luogo ad una maledizione tra le più difficili da tollerare.

Per alcuni anni si è creduto che le cellule prese isolatamente fossero immortali e che soltanto quando si assemblavano a costituir tessuti ed organi erano sottoposte a fenomeni di deterioramento. Al momento l’unico dato certo è che col trascorrere degli anni la porzione degli organi funzionalmente attiva, soprattutto il parenchima, viene progressivamente sostituita da tessuto fibro sclerotico, con una diminuzione irreversibile nei processi di rigenerazione. Alla base di queste osservazioni morfologiche vi sono una serie di continue scoperte di meccanismi molecolari a livello genico con l’interessamento di loci predisposti alle riparazioni cellulari, che nel tempo tendono a funzionare in maniera difettosa. Un parere in contrasto con l’orientamento generale degli studiosi era quello della celebre geriatra rumena Aslan, l’artefice del Gerovital, un prodotto che per decenni ha fatto passare la cortina di ferro a migliaia di ricchi ed attempati occidentali.

Mancano ancora, per la rarità della malattia, studi sulla progeria, un’affezione su base genetica che provoca un invecchiamento precocissimo degli organi di chi ne è colpito senza incidere sull’età mentale. Alla base di questa patologia si suppone l’esistenza di un agente sconosciuto, per quanto specifico. Una sua maggiore conoscenza potrebbe permettere di arrestare o rallentarne l’azione con conseguenze sconvolgenti ed imprevedibili su destino dell’umanità.
By Achille della Ragione  – 07/1/2009 – Tratto da: napoli.com
vedi: Acqua del Corpo + Acidosi + Calcio: Pochi sanno che il cavolo crudo contiene il doppio di calcio del latte intero. Il Calcio è un antiacido per eccellenza.

Un inciso:
Il glucosio (zucchero) e’ un alimento nobile soprattutto per le cellule nervose, ma non per le cellule degli altri tessuti, muscoli, ecc., perche queste ultime si nutrono di lipidi (grassi).
La vecchiaia e’ una perdita della capacita di produrre la melanina (vedi BioElettronica), assieme alla lenta acidosi progressiva che si accumula negli anni con la perdita dei bicarbonati (pH basico).

Alimentazione e vitamine nella terza età
La malnutrizione nella terza età è un fenomeno molto più diffuso di quanto si possa ritenere. Alterazioni del metabolismo, uso difarmaci (NdR: e Vaccini) e scarso appetito possono determinare carenze vitaminiche e indurre un peggioramento del quadro di salute generale.

La ricetta della longevità ?
Ogni anziano è in gran parte frutto della sua storia: fondamentale è l’influenza genetica ma più di tutto conta lo stile di vita adottato negli anni. Se è vero che grazie alla ricerca scientifica e all’introduzione di nuove terapie l’aspettativa di vita è notevolmente cresciuta, è anche vero che terza età non è sempre sinonimo di qualità di vita.
Il processo di invecchiamento è un fenomeno multidimensionale nel quale hanno un ruolo ugualmente importante fattori biologici, psicologici, sociali ed economici. Tra questi, vanno considerati i cambiamenti nella sfera alimentare e nutrizionale che possono complicare il quadro di salute generale.

A partire dalla menopausa per le donne e dall’andropausa per gli uomini, si innesca infatti una serie di alterazioni metaboliche che determinano un decremento del fabbisogno energetico, causa principale di malnutrizione. Gli anziani mostrano generalmente indifferenza e indolenza verso il cibo senza considerare che con il tempo l’apparato digerente diventa meno efficiente nell’utilizzare le proteine, le vitamine e i minerali presenti negli alimenti. vedi Disbiosi
Ad aggravare la situazione, il ricorso di molti anziani a farmaci che possono interferire nello stato nutrizionale, modificando il senso dell’appetito, influendo negativamente sull’assorbimento dei principi nutritivi e variando il tempo di transito.

L’insieme di questi fattori può determinare dunque carenze nutrizionali e vitaminiche importanti che possono provocare a loro volta patologie anche gravi. Integrare l’alimentazione con le vitamine (NdR: e sali minerali) più importanti per la terza età, sempre sotto controllo medico, è quindi la strategia più consigliabile per migliorare la qualità di vita e vivere al meglio la vecchiaia.

Tra le sostanze più importanti per contrastare i processi di invecchiamento cellulare ci sono le vitamine antiossidanti (A, C, E), in grado di proteggere dall’azione dannosa dei radicali liberi: queste molecole «di scarto», prodotte a seguito di varie reazioni chimiche che avvengono all’interno dell’organismo, sono «instabili» in quanto prive di un elettrone e tendono a legarsi con cellule sane provocandone la degenerazione.
A questo riguardo, uno studio pubblicato sull’American Journal of Clinical Nutrition ha dimostrato che una supplementazione con vitamina C, E, beta-carotene e zinco è indicata nei pazienti colpiti da degenerazione maculare senile, mentre un’altra indagine pubblicata sul «Cochrane Database of Systematic Reviews» ha rilevato che supplementazioni di vitamina C possono migliorare le condizioni di anziani affetti da polmonite.
Anche l’apporto di vitamina D è fondamentale per preservare lo stato di salute delle ossa degli anziani. In questi ultimi, infatti, spesso costretti a casa e poco esposti alla luce del sole, si osserva una riduzione della sintesi di questa vitamina a livello epiteliale, che può indurre stati di carenza con ripercussioni sulla struttura ossea e sulle performance fisiche.
Non va infine trascurata l’influenza delle vitamine sulle funzioni cognitive degli anziani.
Secondo un recente studio pubblicato anch’esso sull’American Journal of Clinical Nutrition, acido folico e vitamina B12 svolgono un’azione sinergica per preservare le performance cognitive delle persone più avanti con l’età.
By AA.VV. – Tratto da: http://a0548.gastonecrm.it/newsletter/public/art_83.htm

Dopo una tecnica di disintossicazione, deionizzazione, disinfiammazione e’ opportuno fornire all’organismo, Fermenti lattici multibatterici, prodotti dell’Alveare (miele, pappa reale, propolis) ed aceto di mele con miele (1 cucchiaino di uno e dell’altro)

Ricordiamo che le alterazioni degli enzimi, della flora, del pH digestivo e della mucosa intestinale influenzano  la salute,  non soltanto a livello intestinale, ma anche a distanza in qualsiasi parte dell’organismo.

Se vuoi conoscere il tuo stato di Benessere e migliorarlo con queste speciali apparecchiature modernissime,  che neppure gli ospedali hanno, prenota via mail la consulenza QUI. Esso permette anche di analizzare qualsiasi prodotto esistente e la sua compatibilita’ o meno, con il soggetto analizzato….
vedi anche: Medicina Quantistica
Quindi se volete fare un Test di Bioelettronica (test di controllo del livello di Salute_benessere)….
– scrivete QUI: info@mednat.news

>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>

Il mantenimento di uno stabile giusto rapporto acido-base è una componente vitale dell’omeostasi corporea.
Oltre cento diagrammi, nomogrammi, equazioni e regole sono state introdotti per rappresentare il rapporto acido-base: lungi dal semplificare le cose, queste diverse rappresentazioni hanno contribuito a complicarle a causa dell’introduzione di diversi nuovi termini e definizioni.

Terminologia e definizioni
Molta gente sperimenta difficoltà a capire il rapporto acido-base.
Molte di queste difficoltà derivano dall’assenza di familiarità con la terminologia impiegata. Se noi abbiamo una scarsa comprensione dei comuni termini come neutro, pH, acidosi metabolica, eccesso di basi, ecc., non deve sorprendere che abbiamo anche difficoltà a capire, i concetti, i modelli, le sindromi descritte.
Indicatore acido-base del pH: Piaccametro 
Vedi: Terminologia e definizioni dell’equilibrio acido-base
Continua nel sito: http://www.unipa.it/~lanza/gtai/acido-base/abindexit.html#Rep
vedi anche: http://digilander.libero.it/itisaltamura/arizona/acqua/acidibasi.htmi
Introduzione alla Medicina Naturale

U.S. life expectancy is about 78 years – one of the lowest life expectancies among developed nations. Lower than Cuba’s, and just marginally higher than Slovenia, according to figures from the United Nations.
China’s life expectancy lies around 73 years, which includes the high infant mortality rate of the rural areas. According to the Chinese Municipal Center for Disease Control, the life expectancy in cities like Beijing and Shanghai is about 80 years, and Hong Kong comes in with a life expectancy of over 82 years, despite the many health hazards inherent with living in these over-crowded cities.
Clues to the Chinese secret of longevity can be found in the streets, in the form of morning and evening rituals, involving large masses of people of all ages practicing tai-chi, aerobics, games, and even open air ballroom dancing.
Daily exercise is widespread and woven into the Chinese culture, offering more than just a way to burn calories. It also enforces social interaction, limiting the isolation that so often comes with old age in the United States.
Tratto da: LiveScience.com October 16, 2007
Ma sopra tutto mangiano riso e non pasta e pane !

>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>

Invecchiamento bloccato grazie ad un enzima – 30 Novembre 2010
L’invecchiamento può essere arrestato, secondo recenti ed importanti studi, da un enzima: la telomerasi.
L’azione di quest’ultimo è stata evidenziata da uno studio condotto da un gruppo di ricercatori del Dana-Farber Cancer Institute e dell’Harvard Medical School di Boston (Usa).
Da questa ricerca, pubblicata sulla rivista Nature, si è scoperto che l’enzima telomerasi ha un’azione di ricostruzione dei telomeri.  Cosa sono ?
Questi sono delle sequenze di DNA (codice genetico) che proteggono i cromosomi (elementi che appaiono nel nucleo della celluladurante la divisione cellulare).
Quando le cellule si dividono i telomeri si accorciano, questo meccanismo porta alla fine ad una riduzione talmente drastica, da arrivare all’impossibilità di ulteriori divisioni, fino alla morte cellulare.
Dallo studio condotto sui topi, e seguito dal dottor Ronald DePinho, l’enzima telomerasi riesce ad allungare la vita cellulare e quindi ad inibire l’accorciamento drastico dei telomeri. Questo porta all’interruzione del processo di invecchiamento.
Com’è stato condotto lo studio sui topi ?
I ricercatori hanno privato gli animali dell’enzima telomerasi, provocando loro un invecchiamento precoce.
Dopo di che gli studiosi hanno riattivato l’enzima, notando con grande stupore, che alcuni organi, come i testicoli, che si erano raggrinziti con l’inibizione dell’enzima, sono tornati alla normalità.
Oltre ai testicoli, il “ringiovanimento” si è visto anche in altri organi: milza, intestino, fegato ed anche il cervello. E’ uno studio molto importante che continuerà per essere approfondito e per ottenere risultati sempre migliori.
By Daniele88 – Fonte: tantasalute.it

>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>

DIET, evolution and Aging – European Journal of Nutrition 4O: 200-213 (2001) ©SteinkopffVerlag2001
ORIGINAL CONTRIBUTION L. Frassetto R. C.Morris, Jr. D. E. Sellmeyer K.Todd A. Sebastian
Received: 1O May 2001 Accepted: 23 May 2001
Anthony Sebastian, M. D. (0) – Box 0126 – University of California – San Francisco, CA 94143, USA – E-Mail: sebastia@gcrc.ucsf.edu

The pathophysiologic effects of the post-agricultural inversion of the potassium-to-sodium and base-to-chloride ratios in the human diet

Summary
Theoretically, we hu­mans should be better adapted physiologically to the diet our an­cestors were exposed to during mil­lions of years of hominid evolution than to the diet we have been eating since the agricultural revolution a mere 10,000 years ago, and since in­dustrialization only 200 years ago.
Among the many health problems resulting from this mismatch be­tween our genetically determined nutritional requirements and our current diet, some might be a con­sequence in part of the deficiency of potassium alkali salts {K-base), which are amply present in the plant foods that our ancestors ate in abundance, and the exchange of those salts for sodium chloride (NaCl},which has been incorpo­rated copiously into the contempo­rary diet, which at the same time is meager in K-base-rich plant foods.
Deficiency of K-base in the diet increases the net systemic acid load imposed by the diet. We know that clinically-recognized chronic meta­bolic acidosis has deleterious effects on the body, including growth retardation in children, decreased muscle and bone mass in adults, and kidney stone formation, and that correction of acidosis can ameliorate those conditions. Is it possible that a lifetime of eating di­ets that deliver evolutionarily su-perphysiologic loads of acid to the body contribute to the decrease in bone and muscle mass, and growth hormone secretion, which occur normally with age? That is, are con­temporary humans suffering from the consequences of chronic, diet-induced low-grade systemic meta­bolic acidosis ?
Our group has shown that con­temporary net acid-producing di­ets do indeed characteristically produce a low-grade systemic metabolic acidosis in otherwise healthy adult subjects, and that the degree of acidosis increases with age, in relation to the normally oc­curring age-related decline in renal functional capacity.
We also found that neutralization of the diet net acid load with dietary supplements of potassium bicarbonate (KHCO₃) improved calcium and phosphorus balances, reduced bone resorption rates, improved nitrogen balance, and mitigated the normally occurring age-related de­cline in growth hormone secretion – all without restricting dietary NaCl. Moreover, we found that co-administration of an alkalinizing   salt of potassium (potassium cit­rate) with NaCl prevented NaCl from increasing urinary calcium excretion and bone resorption, as occurred with NaCl administration alone.
Earlier studies estimated dietary acid load from the amount of ani­mal protein in the diet, inasmuch as protein metabolism yields sulfu-ric acid as an end-product. In cross-cultural epidemiologic stud-ies,Abelow (1] found that hip frac­ture incidence in older women cor­related with animal protein intake, and they suggested a causal rela­tion to the acid load from protein. Those studies did not consider the effect of potential sources of base in the diet. We considered that esti­mating the net acid load of the diet (i. e., acid minus base) would re­quire considering also the intake of plant foods, many of which are rich sources of K-base, or more pre­cisely base precursors, substances iike organic anions that the body metabolizes to bicarbonate. In fol­lowing up the findings of Abelow et al., we found that plant food intake tended to be protective against hip fracture, and that hip fracture inci­dence among countries correlated inversely with the ratio of plam-to-animal food intake. These findings were confirmed in a more homoge­neous population of white elderly women residents of the U. S.
These findings support affirma-tive answers to the questions we asked above.
Can we provide dietary guide­lines for controlling dietary net acid loads to minimize or eliminate diet-induced and age-amplified chronic low-grade metabolic acido-sis and its pathophysiological se­quelae.
We discuss the use of algo-evolution and aging rithms to predict the diet net acid and provide nutritionists and clini­cians with relatively simple and re­liable methods for determining and controlling the net acid load of the diet. A more difficult question is what level of acidosis is acceptable.
We argue that any level of acidosis maybe unacceptable from an evolutionarily perspective, and indeed, that a low-grade metabolic alkalo^: sis may be the optimal acid-base state for humans.

Keywords  Acid-base-Nutrition and evolution – Diet net acid load – Protein – Organic anions

Introduction
The nutritional requirements of humans were estab­lished by natural selection during millions of years of in which humans and their hominid ancestors consumed foods exclusively from a menu of wild animals and un­cultivated plants [2,3]. By contrast, the past 10,000 years – less than one percent of hominid evolutionary time -has afforded natural selection insufficient time to gen­erate adaptations and eliminate maladaptations to the profound transformation of the human diet that oc­curred during that period consequent to the inventions of agriculture and animal husbandry, and more recently, to the development of mouern food production and dis­tribution technologies [2-5].
In comparison to the diet habitually ingested by pre-agricultural Homo sapiens living in the Upper Pale­olithic period (40,000 to 10,000 years ago), also referred to as the Late Stone Age, the diet of contemporary Homo sapiens has an overabundance of fat, simple sugars, sodium and chloride, and a paucity of fiber, calcium and potassium [2]. From an evolutionary nutritional per­spective, contemporary humans are Stone Agers habitu­ally ingesting a diet discordant with their genetically de­termined metabolic machinery and integrated organ physiology [6]. This article discusses some of the poten­tial consequences of these changes.

The modern dietary excess of NaCI and deficiency of K⁺ and HCOJ precursors
From extensive data on the diets of existing hunter-gath­erer societies, and from inferences about the nature of the Paleolithic environment, Eaton and Konner analyti­cally reconstructed the Paleolithic diet and estimated the probable daily nutrient intakes of Paleolithic hu­mans [21. In an estimated 3000 kilocalorie diet, meat constituted 35 percent of the diet by weight and plant foods, 65 percent.
Total protein intake was estimated as 251 grams per day, of which animal protein was 191 grams, and plant proteins, 60 grams per day. By contrast, modern humans consume less than one-half that amount of animal protein, and only about one-third that amount of plant protein, per kilocalorie of diet con­sumed [7]. Sodium intake was estimated at about 29 meq per day, and potassium intake, in excess of 280 meq per day. By contrast, modern humans consume between 100-300 meq of sodium per day, and about 80 meq of potassium per day.

That is, in the switch to the modern diet, the K/Na ra­tio was reversed, from 1 to 10, to more than 3 to 1. Since food sodium is largely in the form of chloride salts, and food potassium largely in the fortm of bicarbonate-gen­erating organic acid salts, the C1/HCO₃ ratio of the diet has become correspondingly reversed. Further, the ex­tent to which the dietary K/Na ratio is reversed increases with age [8], and presumably therefore also does the CI/HCO3 ratio. Yet, the biologic machinery that evolved to process these dietary electrolytes remains largely un­changed, genetically fixed in Paleolithic time [2]. Thus, the electrolyte mix of the modern diet is profoundly mismatched to its processing machinery and the extent of the mismatch increases with age. As a consequence of the diet-kidney mismatch, contemporary humans are not only overloaded with Na⁺ and Cl~ but also deficient in K⁺ and HCO₃~. Fig. 1 demonstrates this exchange of monovalent ions.

Adverse effects of excessive dietary sodium chloride
Excessive dietary sodium intake is mostly known to be associated with elevated blood pressure.

Studies in individuals [9-11] as well as populations [12-15] have demonstrated correlations between dietary sodium in­take and both systolic and diastolic blood pressure. Good blood pressure control has been linked with im­provements in cardiac, cerebral and kidney function and in reductions in morbidity and mortality from car­diovascular and renal disease [16-19].

Dietary sodium is a less well-known determinant of urinary calcium excretion. Urinary excretion of calcium is well documented to vary directly with that of Na⁺ [20]. Even a moderate reduction of dietary sodium, from 170 to 70mmol/day, could attenuate not only hypertension but also hypercalciuria, and thereby prevent both kid­ney stones and osteoporosis. That the hypercalciuric ef­fect of excessive dietary sodium may be a preventable cause of osteoporosis would seem supported by the re­sults of recent studies in both post-menopausal women and adolescent girls [21,22}. Abone-demineralizing ef­fect of NaCl-induced hypercalciuria would also be in keeping with the many observations made by Nordin [23, 24] and Goulding and their associates [25, 26], in both humans and rats.

Lack of potassium in the diet

The evolutionarily recent increase in dietary sodium in­take has been reciprocated by a decrease in dietary potassium intake. It has been estimated that our Pale­olithic ancestors ate a diet containing in excess of 200 meq potassium daily [2]. What effects might this lack of potassium in the diet engender ?
As early as 1928, Addison reported that potassium administration could lower elevated blood pressure in humans [27], and some 40 years later,Dahlet al.demon­strated that increasing the ratio of potassium to sodium in the diet of salt-sensitive hypertensive rats lowered blood pressure in a stepwise fashion [28].

In normotensive humans, Morris and colleagues re­cently demonstrated that increases in blood pressure in­duced by sodium loading could be progressively attenu­ated by increasing dietary potassium intake from 30mmol/day to 120mmol/day. In this study, potassium was given as the bicarbonate salt. Interestingly, this de­cline in blood pressure was significantly greater in the 24 African-American males than in the 14 Caucasian males in the study [29], suggesting not just a dietary, but a ge­netic component to the response of blood pressure to potassium bicarbonate irtgestion.
In this same study, supplemental KHCO₃ can also override the hypercalciuric effect of dietary NaCl-load-ing, even though such supplementation further in­creases the urinary excretion of sodium. In a recently re­ported metabolic study of midd!e-aged normal men fed a diet marginally deficient in both K⁺, 30 mmol/d, and calcium, 14 mmol/d, increasing dietary NaCl from 30 to 250 mmol/d induced a 50 % increase in urinary calcium that supplemental KHCO₃ either reversed or abolished, depending on whether it was supplemented to 70 or 120 mmol/d, mid- and high-normal intakes, respectively [29]. As an apparent consequence of its demonstrated natriuretic effect, supplemental KHCO₃ also reversed and abolished, respectively, NaCl-induced increases in blood pressure in these men with such normotensive “salt-sensitivity” (Fig. 2), a precursor of hypertension [30,31], In women fed a normal K⁺ diet, supplemental K-citrate prevented not only the hypercalciuria induced by dietary NaCl-loading, but also prevented an increase in biochemical markers of bone resorption (Sellmeyer, D., et al, unpublished observations).

Specific adverse effects of excessive dietary chloride Although much work has been done on the adverse ef­fects of dietary sodium chloride on blood pressure, very little has been done to explore the specific role of exces­sive dietary chloride. And yet.the chloride content of the modern diet is at least as high as the sodium content [32]. Does the exchange of the bicarbonate we used to eat for the chloride that we presently eat have any ad­verse effects? Morris and colleagues first demonstrated in uninephrectomized rats given deoxycorticosterone that while treatment with sodium as a combination of the bi­carbonate and acetate salt raised blood pressure, treat­ment with sodium as the chloride salt raised blood pres­sure to a significantly higher level [33]. Luft et al. demonstrated that sodium as the chloride salt raised blood pressure in stroke-prone spontaneously hyper­tensive rats [34] and sodium as the bicarbonate salt low­ered blood pressure in mildly hypertensive humans [35], More recently, Morris et al. have done studies in­vestigating the effects of KC1 and KBC (potassiumbicarbonate) on blood pressure, frequency of stroke and severity of the renal lesions in the SHRSP [36]. Rats treated with KCI had significantly higher PRA than rats treated with KBC. In each group and in all combined, the severity of hypertension was highly cot related with the levels of PRA (log transformed). KCI loading induced greater increases in BP than in control or KBC rats (Fig. 3)

The incidence of strokes was significantly higher with KCI than with KB/C (Table 1). In the KC1/KBC rates, strokes occurred only in animals with SBP > 248 mmHg and with PRA > 26.5 ng/ml/h (logPRA=1.42).

Light microscopic examination of the kidneys re­vealed glomerular, tubular, interstitial, and vascular le­sions (histologically ranked in combination) similar in quality but significantly more frequent and more severe with KCI supplementation than either KB/C or CTL [36]. Irrespective of dietary supplements, renal lesions were rare in rats with SBP < 200 mmHg* The overall severity of renal lesions was highly correlated with the level of PRA (log transformed) (R²= 0.67, p < 0.0001). Protein-uria was significantly greater with KCI than either KB/C or CTL (Table 1). Creatinine clearance was significantly greater in KB/C than in KCI or CTL (Table 1). Morris and colleagues concluded that the extent of renal damage and likelihood of stroke are determined by the severity of hypertension.

Diet and acid-base

In contrast to its excess chloride content, the modern diet lacks bicarbonate and anion precursors that gene­rate bicarbonate on metabolism. As a consequence, the net acid load of the modern diet is higher than it would otherwise be. The rest of this article will discuss this bi­carbonate-deficiency-mediated dietary acid excess.

Endogenous acid production
Endogenous acid production can be considered as com­prising three components: 1) organic acids produced during metabolism that escape complete combustion to.

Table 1  Effects of KCI vs. KB/C in SHRSP before and 15 Weeks after initiation of dietary supplements

SBP, DBP, PRA, UV-Protein: median and (95% CIJ
Renal lesions, creatinine clearance, UV-Na, BW: mean(±SD)
1 Data not available from 2 rats who had died of stroke.
*p < 0.05; KCI vs. either KB/C or CTL, **p < 0.05; KB/C vs. either KCI or CTL, ⁺p < 0.05; KCI vs. KB/C.

Endogenous acid production

Endogenous acid production can be considered as com­prising three components: 1) organic acids produced during metabolism that escape complete combustion to carbon dioxide and water; 2) sulfuric acid (H₂SO₄) pro­duced from the catabolism of methionine and cystine, the sulfur-containing amino acids in dietary proteins; and 3) potassium bicarbonate (KHCO₃) produced from the metabolism of the potassium salts of organic anions in the vegetable foods of the diet, for example potassium citrate and potassium malate. The potassium bicarbon­ate so produced titrates sulfuric and organic acid and thereby downregulates net endogenous acid production (NEAP).

NEAP then is computed as the sum of organic acid production and sulfuric acid production minus the in-testinally absorbed potassium salts of organic anions that are metabolized to potassium bicarbonate.

All foods contain sulfur-containing amino acids, al­though fruits in general contain very little; animal prod­ucts and cereal grains contain very little or no potential base – this comes mainly from fruits and other non-grain plant foods. Organic acid production is driven in part by the quantity of base-precursors in the diet, so in­creasing dietary base precursors does not yield equiva­lent reductions in NEAP. The greater the quantity of or­ganic and sulfuric acids produced from metabolism, and the lower the amounts of potassium salts metabolizable to bicarbonate, the greater the NEAP.

Estimating the diet net acid load

It is possible to quantify NEAP in normal subjects in­gesting whole food diets by measurements of the quan­tity of the inorganic constituents of diet, urine and stool, and of the total organic anion content of the urine [37]. However, such studies are extremely time-consuming and labor-intensive. Kurtz et al. utilized renal net acid excretion (RNAE) as a quantitative index of NEAP, since under steady-state conditions there is a predictable rela­tion between these two variables [37,38], and since net add excretion is more readily measured. Nearly 90 % of the variance in net acid excretion among the subjects was accounted for by differences in net endogenous acid production (Fig. 4).

Measuring RNAE to estimate NEAP of whole food di­ets was first used about 90 years ago [39]. Volunteers ate large amounts of one particular food item for approxi­mately one week, while doing sequential 24-hour urine collections, which were then analyzed for ammonia, titratable acids and total carbon dioxide – the con­stituents of RNAE. This approach has a number of draw­backs; not only is it tedious and time-consuming, but as Blatherwick wrote in his article discussing the effects of a boiled cauliflower diet, “It became very distasteful af­ter the third day, so that the experiment was discontin­ued.”

Methods of estimating diet net acid load solely from dietary intake have also been developed. Remer and Manz developed an algorithm for calculating net acid excretion using a formula that estimated net intestinal absorption of cations and anions, organic acids and sul-fate. In this study, RNAE as determined by the formula I (Cl- + P¹–⁸– + SO₄ + OA – Na⁺ – K⁺ – Ca²⁺ – Mg²⁺) cor­related reasonably well with the measured NAE [40]. Us­ing a similar formula, Remer and Manz also calculated the potential acid load for individual food items [41].

Frassetto et al. developed a somewhat less involved but nearly as precise method, using an algorithm to pre­dict diet acid load from only two diet constituents: diet protein and potassium content [42].
Data from healthy subjects at steady-state, eating one of 20 whole food di­ets as part of metabolic balance studies that measured RNAE were analyzed; both dietary protein and dietary potassium intake were demonstrated to be independent predictors of RNAE, when evaluated by multiple regres­sion analysis. Because protein and potassium were not correlated to each other, the ratio of dietary protein to potassium was evaluated. This ratio correlated signifi­cantly with the difference between the sulfur (i. e., po­tential acid) and potential base contents of the diets (Fig. 5 A & B), and accounted for 70-75% of the varia­tion in RNAE of the diets studied.

Acid-base balance in normal humans
Three factors have been found to be independent pre­dictors of the set point for blood hydrogen ion and bi­carbonate concentration; the partial pressure of carbon dioxide, NEAP and age. Madias et al. [43] were the first to propose that the interindividual differences in plasma acidity in normal subjects can be accounted for in part by corresponding differences in the level at which plasma PCO2 is regulated by the respiratory system in response to factors other than those entrained by changes in plasma acidity itself. In normal subjects they observed a positive correlation between plasma [H⁺] and plasma PCO2 among subjects.
Kurtz et al. [44] were the first consider whether “metabolic” factors might also play a role in determin­ing the interindividual differences in plasma acidity and plasma [HC0₃“] in normal subjects. At steady-state, there was a significant direct relationship between plasma acidity and RNAE, and a significant inverse rela­tionship between plasma [HCCV] and RNAE, after ad­justing for the effects of interindividual difference in the respiratory set-point for PCO₂. Subsequently, Frassetto et al. [45] extended these findings to a larger number of subjects and a wider variety of diets. Adding bicarbon­ate to the diet sufficient to reduce RNAE to nearly zero significantly reduced blood [H+] and increased plasma [HCCV] [46].

Frassetto et al. subsequently carried out a systematic analysis of measurements of blood [H⁺] and PCO₂, plasma [HCCV], RNAE and glomerular filtration rate (GFR, estimated as 24-hour creatinine clearance) in 64 healthy adult men and women over a wide range of ages, at steady-state on a controlled diet while residing in a clinical research center [45]. Those studies identified age as a significant determinant of the blood acid-base com­position in adult humans. From young adulthood to old age (17-74 years), otherwise healthy men and women develop a progressive increase in blood acidity and de­crease in plasma [HCCV], indicative of an increasingly worsening low-grade metabolic acidosis (Fig. 6 A & B). The age effect was significant even when the effects of differences among subjects in diet net acid load were ad­justed for. Indeed, age and diet net acid load (reflected in steady-state RNAE) were independent co-determinants of the degree of metabolic acidosis. In comparing the relative impact of age and diet net acid load, over their respective ranges (17-74 years, 15-150 meq/day), age had -1.6 times greater effect on blood [H⁺] and plasma [HCCV] than diet net acid load. Increasing age therefore substantially amplifies the chronic low-grade metabolic acidosis induced by diet.
Age and GFR were highly correlated, and were not in­dependent predictors of blood acidity or plasma bicar­bonate.
One explanation may be that renal acid-base regulatory function tends to decline with increasing age [47,48]. Thus, as we age, renal acid-base regulatory function declines and the degree of diet-induced metabolic acidosis increases.

Pathophysiologic consequences of severe metabolic acidosis in humans
Before discussing the possible effects of the mild meta­bolic acidosis produced by age and diet, let us briefly re­view some of the effects on the body of more severe metabolic acidosis, such as that associated with ad­vanced renal failure or in experimental loading studies with ammonium chloride. It is well recognized that se­vere metabolic acidosis can cause pathophysiologic con­sequences in humans. Long term increases in acid loads have been shown to affect multiple systems.

Chronic acidosis and bone
Loss of bone substance is a well-known pathophysio-logic consequence of severe metabolic acidosis [49,50]. Bone is a large reservoir of base in the form of alkaline salts of calcium (phosphates, carbonates), and those salts are mobilized and released into the systemic circu­lation in response to increased loads of acid [51-54]. The liberated base mitigates the severity of the attendant systemic acidosis, contributing to systemic acid-base homeostasis. The liberated calcium and phosphorus are lost in the urine, without compensatory increase in gas­trointestinal absorption, and reduce bone mineral con­tent [51,53,55,56]. Reduction of bone mineral content occurs as an unavoidable disadvantage of the participa­tion of bone in the body’s normal acid-base homeosta-tic response to the acid load.
The response of bone to acute acidosis has been stud­ied most extensively by Bushinsky and coworkers using a variety of in vitro models. Acute metabolic acidosis promptly results in buffering of hydrogen by bone car­bonate, with attendant release of sodium, potassium and calcium [57-59].
When acid loading continues over days to weeks, bone continues to participate in systemic acid-base homeostasis, slowing the acidward shift in systemic acid-base equilibrium, to its own detriment [51-53].Net external acid balance remains positive, indicating con­tinuing internal buffering of the net acid load. Mobiliza­tion of bone base persists, and the bone minerals (cal­cium and phosphorus) accompanying that base continue to be wasted in the urine, without compen­satory increases in intestinal absorption [60]. With chronicity of the acidosis, bone mineral content and bone mass progressively decline [61,62] and osteoporo­sis develops [61,63,64].

The destructive process is not only a passive physi-cochemical dissolution of bone mineral by acidic extra­cellular fluid, but also an active process involving cell-mediated bone resorption and formation signaled by increased extracellular fluid [H⁺] and decreased [HCO3-]¹ [65-67]. Extracellular acidification increases the activity of osteoclasts.the cells that mediate bone re­sorption [65-67], and suppresses the activity of os-teoblasts, the cells that mediate bone formation [65].
Not only the mineral phase, but also the organic phase of bone, is lost during chronic acidosis. Release of bone mineral by osteoclasts is accompanied by osteo-dastic degradation of bone matrix[50, 61, 63, 64].
In chronic acid loading studies in humans, urinary hy-droxyproline excretion increases [46,51],and serum os-teocalcin levels decrease [46], suggesting that matrix re­sorption increased and formation decreased.

Chronic acidosis and calcium excretion
Even mild reductions of plasma [HCO₃‘] and arterial pH to values still within their normal range also induce an increase in urinary calcium, negative calcium balance [46] and a reduction in urinary citrate [68].
It has been suggested that a reduced urinary excretion of citrate may be useful in identifying such low-grade metabolic acidosis (vide infra).

1 Chronic respiratory acidosis, in which acidemia but not hypobicar-bonatemia occurs, is not accompanied by increased urinary excre­tion of calcium and phosphorus [100]

In fact, supplemental KHCO₃ in amounts that can be predicted to induce only a modest increase in the plasma bicarbonate concentration, but one still attenuating of low-grade metabolic acidosis (vide infra) [46], can both induce a positive calcium bal­ance, by reducing the urinary excretion of calcium, and reduce the formation of kidney stones, apparently by also correcting hypocitraturia [69]. Supplemental K-cit-rate and KHCO₃ are effective in reducing the urinary ex­cretion of calcium and in increasing the urinary excre­tion of citrate presumably because both alkaline salts induce equal increases in plasma bicarbonate [68].
In patients with classic RTA.bicarbonate therapy that sustains correction of frank metabolic acidosis not only reduces the formation of calcium-containing kidney stones, but also induces a positive calcium balance [70, 71] and can induce healing of osteomalacia [72].
Furthermore, with bicarbonate therapy in children with classic RTA, can correct hypercalciuria and im­prove somatic growth, even when severe stunting has al­ready occurred [73, 74]. Bicarbonate therapy has been found to induce these effects only when provided in suf­ficient amounts to maintain the plasma bicarbonate at concentrations well within the normal range. These amounts must be great enough both to offset the renal bicarbonate wasting that characterizes classic RTA in rapidly growing children, and to titrate their endoge-nously produced non-volatile acid [73]

Chronic acidosis and skeletal muscle nitrogen metabolism and renal nitrogen excretion
In disorders that cause chronic metabolic acidosis, protein degradation in skeletal muscle is accelerated [75-77], which increases the production of nitrogen end-products that are eliminated in the urine, thereby inducing negative nitrogen balance [77]. This disturb­ance of nitrogen metabolism apparently results directly from the acidosis, not its cause, nor from other sequelae of the underlying acidosis-producing disorder, because it occurs with widely differing acidosis-producing con­ditions [77-79] and because it is reversible by adminis­tration of alkali [80-82], which corrects the acidosis but not its cause.

Acidosis-induced proteolysis appears to be an acid-base homeostatic mechanism. By releasing increased amounts of amino acids, including glutamine and amino acids that the liver can convert to glutamine, which is the major nitrogen source used by the kidney for synthesis of ammonia, the kidney can increase the excretion of acid (as ammonium ion) in the urine, thereby mitigating the severity of the acidosis [76, 77, 83].
Metabolic acidosis induces nitrogen wasting in part by directly increasing the rate of protein degradation in
skeletal muscle, without commensurately increasing the rate of protein synthesis [75,76].

Chronic acidosis and growth hormone
More severe forms of metabolic acidosis from renal tubular acidosis and chronic renal failure in children are associated with low levels of growth hormone, and their height arid weight are often below the 5^th percentile for age. In 6 pediatric subjects with chronic renal failure and 6 subjects with renal tubular acidosis, Caldas and col­leagues demonstrated that treatment with enough bi­carbonate to correct the pH and plasma bicarbonate levels to normal causes both 24-hour mean growth hormone and IGF-1, a growth-related hormone, to dou­ble, from 2.7±0.2 to 4.8±0.2 and 156±17 to 271±19 re­spectively (p < 0.001) [84]. As mentioned above, treating children with RTA with potassium citrate, who are short and have weak bones, causes them to start growing at a normal rate and to attain normal stature [73]. Brunnger et al. [85] report that experimentally induced, chronic metabolic acidosis in humans results in hepatocellular resistance to growth hormone and consequent reduc­tion in serum IGF-1 levels, and Mahlbacher subse­quently showed that driving IGF-1 production with exogenous growth hormone could correct acidosis-in-duced nitrogen wasting [86]

Pathophysiologic consequences of diet-induced, age-amplified chronic low-grade metabolic acidosis in humans
It is understandably difficult to think “metabolic acido­sis” when the values for plasma acid-base composition are in the range traditionally considered normal, though clinicians are accustomed to considering metabolic aci­dosis under those circumstances in the context of diag­nosing “mixed” acid-base disorders.
The term “meta­bolic acidosis” implies pathophysiologic sequelae. If such sequelae were not present with normal diet net acid loads, one might remain skeptical about the appropri­ateness of the term. But, as discussed in this next section, such acidosis-induced pathophysiological conditions as negative calcium and phosphorus balance, accelerated bone resorption, and renal nitrogen wasting appear to be consequences of the normal diet acid load, as they are significantly improved by “normalizing” blood acid-base composition by neutralizing the diet net acid load with small amounts of exogenous base [46,87,88].
Although the degree of diet-induced, age-amplified metabolic acidosis maybe mild as judged by the degree of perturbation of blood acid-base equilibrium from currently accepted norms, its pathophysiologic signifi­cance cannot be judged exclusively from the degree of that perturbation. Adaptations of the skeleton, skeletal muscle, kidney and endocrine systems that serve to mit­igate the degree of that perturbation impose a cost in cu­mulative organ damage that the body pays out over decades of adult life [89,90].

Evidence that diet-induced metabolic acidosis mobilizes skeletal base
In the studies referred to in the previous section, the ef­fects of metabolic acidosis were studied in response to large exogenous acid loads. What is the evidence that bone contributes to acid-base homeostasis in subjects with the chronic low-grade metabolic acidosis that re­sults from eating a normal, net acid-producing diet ?
For any level of acid loading, if bone is contributing to acid-base homeostasis, even though blood acid-base equilibrium appears to be stable, not all of the daily net acid load should be recoverable in the urine [51,52], i. e., acid should appear to be accumulating in the body on a daily basis. As discussed earlier, continued acid reten­tion in normal subjects has been demonstrated at diet net acid loads within the normal range.
The stability of the blood acid-base equilibrium is de facto evidence of the existence of an internal reservoir of base that con­tinually delivers base to the systemic circulation in an amount equal to the fraction of the net acid load that the kidneys fail to excrete. Bone is the major such internal reservoir of base known to exist.

Another way to test whether persisting bone loss oc­curs in response to chronic low-level diet-induced meta­bolic acidosis is to examine the effect of neutralizing the diet net acid load by addition of exogenous base. Such studies have been carried out in postmenopausal women [46].Potassium bicarbonate,when administered in doses that nearly completely neutralize the diet net acid load, reduces urinary wasting of calcium and phos­phorus, improves preexisting negative balances of cal­cium and phosphorus, and as indicated by biochemical markers, reduces the rate of bone resorption and stimu­lates the rate of bone formation [46]. Lemann [91] like­wise demonstrated significant improvement in calcium and phosphorus balances when the diet net acid load was neutralized during potassium bicarbonate adminis­tration in humans.
Thus, two lines of evidence indicate that chronic low-level diet-induced acidosis imposes a chronic drain on bone: a) stability of blood acid-base equilibrium in the face of continuing retention of acid, and,b) amelioration of negative calcium and phosphorus balances, reduction of bone resorption and stimulation of bone formation attendant to neutralization of the dietary acid load.

Evidence that diet-induced metabolic acidosis, is a factor in the pathogenesis of clinical osteoporosis
If chronic low-level diet-induced metabolic acidosis im­poses a chronic, clinically significant drain on bone mass, it might be possible to account in part for diffe­rences in bone mass among individuals by differences in the net acid load from their habitual diets. Unfortu­nately, the measurements of net acid production or ex­cretion rates needed to test that possibility directly are not currently available. It is possible, however, to obtain indirect but still realistic estimates of the differences in diet net acid load among select groups of individuals, and to relate those to differences in rate of bone mass among those groups.
Specifically, it is possible to estimate the differences in diet net acid load among the residents of different countries. That can be accomplished using international food consumption data compiled by the United Nation’s Food and Agricultural Organization (FAO). For each of some 130 countries, FAO tables report consumption of vegetable and animal foods in units of daily per capita vegetable and animal protein consumed. Many vegetable foods are rich in potassium salts of organic anions [92] that can be metabolized to the base, bicarbonate, which in turn reduces the net rate of endogenous ac’d produc­tion for a given rate of acid production from animal foods [39,93, 94]. Animal foods have a relatively lower content of potassium and organic anions. Per unit pro­tein, the potassium content of many vegetable foods ex­ceeds that of animal foods by more than an order of magnitude. Because organic anion content of foods par­allels that of potassium, the content of base precursors also is substantially greater in those vegetable foods than in animal foods. For a given total protein intake, therefore, the ratio of vegetable-to-animal protein con­sumed can provide a rough index for comparison of the base-to-acid-generating potential of the diet among the differing countries.

It is also possible to approximate differences in bone mass among countries.based on published reports of the incidence of hip fractures in women over the age of 50 years. Hip fracture incidence is a good index of bone mass because bone mass is a major determinant of the in­cidence of fractures of bone in older individuals. So, if chronic low-level diet-induced metabolic acidosis im­poses a chronic, clinically significant drain on bone mass, it might be possible to account in part for differences in hip fracture incidence among countries by differences in the ratio of vegetable-to-animal protein consumed.
Fig. 7 depicts the results of such an analyses for the 33 countries in which both hip fracture incidence and per capita food consumption data were available as of 1999 [95]. Note that there is a strong nonlinear relation be­tween fracture incidence and ratio of vegetable-to-ani­mal protein consumed.

Over two-thirds (r2=0,70) of the total variability in hip fracture incidence among coun­tries can be accounted for by its correlation with the ra­tio of base-generating (vegetable) to acid-generating (animal) foods consumed. Countries with the lowest ra­tio of vegetable-to-animal protein intake have the high­est incidence of hip fracture, and vice versa.
This finding provides evidence that dietary base deficiency relative to acid load is a factor in the pathogenesis of the decline in bone mass that occurs with age. Given that low-grade metabolic acidosis of severity proportionate to the diet net acid load is to be expected, this finding supports the hypothesis that diet-induced chronic low-grade meta­bolic acidosis is a factor in the pathogenesis of clinical osteoporosis.

Recently Sellmeyer et al. have reexamined the rela­tionship between the ratio of vegetable-to-animal food intake and hip fracture rates in a more homogeneous population (white elderly women residents of the U. S), and found a similar result [96]. In addition, they found, with repeated measures of hip bone mineral density, that the rate of bone loss in the subjects was greatest in those with the lowest vegetable-to-animal food intake ratio. Those studies are significant because they elimi­nate the confounding effects of racial and cultural fac­tors on hip fracture risk unavoidable in the cross-cul­tural study [95], arid support the hypothesis that chronic low-grade diet-induced metabolic acidosis accelerates bone loss rates in humans.

Using a less indirect index of diet net acid load, namely the ratio of dietary protein-to-potassium [42], New and associates recently reported their observations on bone health in elderly Scottish women to include es­timates of dietary net acid load [97]. The values for lum­bar spine mass were lower and the values of urinary ex­cretion of bone resorption markers were higher in those women in the highest quartile of net acid load, com­pared to those in the lowest quartile. Further, the net acid load was significantly higher in the group of sub­jects who had sustained fractures during the observa­tion period, compared to those who had not.

Evidence that diet-induced metabolic acidosis effects renal nitrogen excretion in humans
Frassetto and coworkers also explored the possibility that nitrogen wasting might occur even with the low-grade “tonic” background metabolic acidosis that ac­companies eating a typical net acid-producing diet [87]. In postmenopausal women, correcting their diet-in­duced low grade metabolic with potassium bicarbonate in amounts that just neutralized their daily diet net acid load, reduced in urinary ammonium excretion, which returned to control when the acidosis was allowed to re­cur by discontinuing the KHCO₃ supplement (Fig. 8). But, in addition to the reduction in ammonia nitrogen excretion during KHCO3 administration, a sustained re­duction in urea nitrogen excretion also occurred, sug­gesting that the higher pre-treatment urea nitrogen ex­cretion rates were contributing to the acidosis-induced nitrogen wasting (Fig. 8). The reductions in urea and ammonia excretion contributed about equally to the ni­trogen sparing effect.

The most straightforward interpretation of these findings is that KHCO₃ administration reduced NEAP and corrected the pre-existing low-grade metabolic aci­dosis, reducing the total rate of renal ammonia produc­tion and, by raising urine pH, reducing intraluminal trapping of ammonium ion. As a consequence, both the excretion of ammonia in the urine and the delivery of ammonia to the systemic circulation via the renal vein decreased. The reduction in urine ammonia contributed directly to improvement in nitrogen balance.
The reduc­tion in ammonia delivery to the systemic circulation via the renal vein contributed indirectly to improvement in nitrogen balance by limiting substrate (viz., ammonia) availability for hepatic urea production [98], thereby re­ducing external loss of nitrogen as urinary urea. And by correcting the pre-existing low-grade metabolic acido­sis, KHCO3 decreased the pre-treatment rate of muscle proteolysis, further contributing to the improvement in nitrogen balance. The magnitude of the KHCO₃-induced nitrogen sparing effect was potentially sufficient to both prevent continuing loss of muscle mass and to restore previously accrued deficits.

Evidence that diet-induced metabolic acidosis effects growth hormone excretion in humans
Frassetto and coworkers also explored the possibility that growth hormone excretion might be affected by this same low-grade “tonic” background metabolic acidosis [87]. In postmenopausal women, correcting their diet-induced low grade metabolic with potassium bicarbon­ate in amounts that just neutralized their daily diet net acid load, was accompanied by an increase in 24-hour mean growth hormone secretion.
The average total serum GH secretion, calculated as the 24-hour inte­grated serum GH concentration, increased from 826±548 pg/ml before KHCO₃ to 915±631 pg/ml after KHCO3 supplementation (p < 0.05), approximately an 11 % increase over baseline. Was this physiologically sig­nificant? Consistent with the effect of growth hormone on bone metabolism, osteocalcin levels also rose in nearly every subject after KHCO₃ supplementation, and were higher at nearly all time points. The 24-hour mean osteocalcin level rose from 7.0±0.9 to 8.3±1.2 ng/ml af­ter KHCO3 treatment (p < 0.005).

Stone age diets for the 21^st century ?
Increasingly, nutritionists are directing attention to the potential detrimental health effects of the major trans­formation of the human diet that occurred relatively re­cently in evolutionary time [99], viewing them as the ef­fects of a conflict of the encounter of old genes with new fuels [3]. Our group is emphasizing the potential conflict between our old genes and new levels of K-base and NaCl in our diet, an insufficiency of the former and over-sufficiency of the latter. In this effort, much remains to be understood, and many interesting questions can be formulated. The subtitle above is one such question. What is the optimal NaCl intake for humans under ordi­nary circumstances ? Does adding NaCl to the diet really make much difference if K-base intakes are optimal ? What are optimal K-base intakes ? Was the Paleolithic diet net base-producing ?
Is the optimal systemic acid-base status of humans a low-grade diet-induced chronic metabolic alkalosis without potassium deficiency ?
Should we increase our protein intakes and balance the acid effects with increased K-base ?

Prospects
Based on the studies and arguments reviewed here, it seems reasonable to expend further effort to investigate the extent of the modulating effect of dietary NaCl and K-base on the expression of osteoporosis, age-related decline in muscle mass, kidney stones, and perhaps age-related decline in renal function.
Re-exchanging the NaCl in our present diet for the K-base that our ances­tral Homo and pre-Homo hominid species ate in abun­dance can be shown to correct diet-induced low-grade metabolic acidosis, and the consequent biochemical ev­idences of decreased growth hormone secretion, in­creased bone resorption with decreased bone formation and increased protein catabolism. Beyond that, the sup­plementation of the diet with K-base can override the ef­fects of NaCl loading on blood pressure and urinary cal­cium excretion.
Thus, increasing dietary K-base to levels approaching those of our stone-age forebears, either with fruits and non-grain plant foods, or with supple­mental K-base, would seeift to hold particular promise for preventing or delaying expression of these age- and diet-related diseases and their consequences.

Acknowledgments This work was supported by the UCSF/Moffitt General Clinical Research Center (NIH grant MOl RR-00079) and by NIH grants RO1-AG/AR0407 and RO1-HL64230.

References

1. Abelow BJ, Holford TR, Insogna KL (1992) Cross-cultural association be­tween dietary animal protein and hip fracture: a hypothesis. Calcif Tissue Int 50:14-18
2. Eaton SB, Konner M (1985) Paleolithic nutrition. A consideration of its nature and current implications. N Engl J Med 312:283-289
3. Neel JV (1999) When some fine old genes meet a ‘new’ environment. In: Simopoulos A (ed) Evolutionary as­pects of nutrition and health. Karger, Basel.pp 1-15
4. Eaton SB, Cordain L (1997) Evolution­ary aspects of diet: old genes, new fuels. Nutritional changes since agriculture. World Rev Nutr Diet 81:26-37
5. Cordain L (1999) Cereal grains:human­ity’s double-edged sword. In: Simopou­los A (ed) Evolutionary aspects of nu­trition and health. Karger, Basel, pp 19-73
6. Eaton SB, Konner M, Shostak M (1988) Stone agers in the fast lane: chronic de­generative diseases in evolutionary per­spective. Am J Med 84:739-749
7. Smit E, Nieto FJ, Crespo CJ, Mitchell P (1999) Estimates of animal and plant protein intake in US adults: results from the Third National Health and Nutri­tion Examination Survey, 1988-1991. J Am Diet Assoc 99:813-820
8. Frisancho AR, Leonard WR (1984) Blood pressure in blacks and whites and its relationship to dietary sodium and potassium intake. ]  Chron Dis 37:515-519
9. Dahl LK (1972) Salt and hypertension. Am J Clin Nutr 25:231-244
10. Kawasaki T, Delea CS, Barttet FC, Smith H (1978) The effect of high-sodium low-sodium intakes on blood pressure and other related variables in human subjects with idiopathic hypertension. Am I Med 64:193-198
11. Myers JB, Morgan TO (1984) Effect of alteration in sodium chloride intake on blood pressure of normotensive subjects. J Cardiovasc Pharmacol 6: S204-S209
12. Chalmers I.Morgan T.DoyleA.Dickson B, Hopper J, Mathews J, Matthews G, Moulds R, Myers J, Nowson C, Scoggins B, Stebbing M (1986) Australian Na­tional Health and Medical Research Council Dietary salt study in mDd hypertension. I Hypertens 4 (suppl 6): s629-s637
13. Gleibermann L (1973) Blood pressure and dietary salt in human populations. Ecol Food Nutr 2:143-156
14. Oliver WJ, Cohen EL, Neel JV (1975) Blood pressure, sodium intake, and sodium   related   hormones   in   the Yanomamo Indians, a “no-salt” culture. Circulation 52:146-151
15. Poulter N, Khaw KT, Hopwood BE, Mugambi M, Peart WS, Sever PS (1984) Salt and blood pressure in various pop­ulations. J Cardiovasc Pharmacol  6 (Suppl l):S197-S203
16. Australian NatlHlth Res Council (1989) Fall in blood pressure with modest re­duction in dietary salt intake in mild hypertension. Lancet 1:399-402
17. Fodor  IG, Whitmore  B, Leenen  F, Larochelle P (1999) lifestyle modifica­tions to prevent and control hyperten­sion. 5. Recommendations on dietary salt. Canadian Hypertension Society, Canadian Coalition for High Blood Pressure Prevention and Control, Labo­ratory Centre for Disease Control at Health Canada, Heart and Stroke Foun­dation of Canada. CMA] 160:S29-S34
18. Yamori Y, Nara Y, Mizushima S, Sawa-mura M, Horie R (1994) Nutritional factors for stroke and major cardiovas­cular diseases: international epidemio-logical comparison of dietary preven­tion [see comments]. Health Rep 6: 22-27
19. Peterson  JC, Adler  S, Burkart  JM, Greene T, Hebert LA, Hunsicker LG, King AI, Klahr S, Massry SG, Seifter )L (1995) Blood pressure control, pratein-uria, and the progression of renal dis­ease. The Modification of Diet in Renal Disease Study. Ann Intern Med 123: 754-762
20. BurtisWJ, Gay L, Insogna KL, Ellison A, Broadus AE (1994) Dietary hypercalci-uria in patients with calcium oxalate kidney stones. Am J Clin Nutr 60: 424-429
21. Cappuccio FP, Meilahn E, Zmuda JM, Cauley JA (1999) High blood pressure and bone-mineral loss in elderly white women:  a prospective  study. Study of Osteoporotic  Fractures  Research Group. Lancet 354:971-975
22. Devine A, Criddle RA, Dick IM, Kerr DA, Prince RL (1995) A longitudinal study Of the effect of sodium and cal­cium intakes on regional bone density in postmenopausal women. Am J Clin Nutr 62:740-745
23. Nordin BEC.PolleyKJ (1987) Metabolic consequences of the menopause. Calcif Tissue Int 4US1-S59
24. Nordin BEC, Need AG, Morris HA, Horowitz M (1992) Sodium, calcium and  osteoporosis. In: Burkhardt P, Heaney R (eds) Nutritional aspects of osteoporosis. Raven Press, New York, pp 279-295
25. Goulding A (1990) Osteoporosis: why consuming less sodium chloride helps to conserve bone. N Z Med J March 18:120-122
26. McParland BE, Goulding A, Campbell AJ (1989) Dietary salt affects biochemi­cal markers of resorption and forma­tion of bone in elderly women. Br Med J 299:834-835
27. AddisonWLT (1928) The use of sodium chloride, potassium chloride, sodium bromide, and potassium bromide in cases of arterial hypertension which are amenable to potassium chloride. Can Med Assoc J 18:281-285
28. Dahl LK, Leiti G, Heine M (1972) Influ­ence of dietary potassium and sodium/ potassium molar ratios on the develop­ment of salt hypertension. J Exp Med 136:318-330
29. Morris RC, Jr., Sebastian A, Forman A, Tanaka M, Schfflidlin O (1999) Nor­motensive salt sensitivity: effects of race and dietary potassium. Hyperten­sion 33:18-23
30. Sullivan JM (1991) Salt sensitivity: def­inition, conception, methodology, and long-term  issues.  Hypertension  (17 Suppl):I61-168
31. Luft FC, Miller JZ, Grim CE, Fineberg NS, Christian JC, Daugherty SA, Wein­berger   MH   (1991)   Salt   sensitivity and resistance of blood pressure: age and race as factors in physiological responses. Hypertension  (17  Suppl): 1102-1108
32. Al-Bander SY, Nix L, Katt R, Korn M, Sebastian A (1988) Food chloride dis­tribution in nature and its relation to sodium content J Am Diet Assoc 4: 472-475
33. Kurtz TW, Morris RC, Jr. (1983) Dietary chloride as a determinant of sodium-dependent hypertension. Science 22: 1139-1141
34. Luft FC, Steinberg H, Ganten U, Meyer D, Gless KH, Lang RE, Fineberg NS, Rascher W, Unger T, Ganten D (1988) Effect of sodium chloride and sodium bicarbonate   on  blood   pressure   in stroke-prone spontaneously hyperten­sive rats. Clin Sci 74:577-585
35. Luft FC, Zemel MB, Sowers JA, Fineberg NS, Weinberger MH (1990) Sodium bi­carbonate and sodium chloride: effects on   blood   pressure   and   electroyte homeostasis in normal and hyperten­sive man. J Hypertens 8:663-670
36. Tanaka M.SchmidlinO, Olson JL,YiSL, Morris RC (2001) Chloride-sensitive re­nal microangiopathy in the stroke-prone spontaneously hypertensive rat Kidney Int 59:1066-1076
37. Lennon EJ, Lemann J, Jr., Iitzow JR (1966) The effect of diet and stool com­position on the net external acid bal­ance of normal subjects. J Clin Invest 45:1601-1607 European Journal of Nutrition, Vol. 40, Number 5 (2001) © Steinkopff Verlag 2001
38. Relman AS, Lennon EJ, Lemann J, Jr. (1961) Endogenous production of fixed acid and the measurement of net bal­ance of acid in normal subjects. J Clin Invest 40:1621-1630
39.  BlatherwickNR(1914)Thesperificrole of foods in relation to the composition of the urine. Arch Int Med 14:409-450
40. Reiner T, Manz F (1994) Estimation of the renal net acid excretion by adults consuming diets containing variable amounts of protein. Am J Clin Nutr 59:1356-1361
41. Remer T, Manz F (1995) Potential renal acid load of foods and its influence on urine pH. J Am Diet Assoc 95:791-797
42. Frassetto LA, Todd KM, Morris RC, Jr., Sebastian A (1998) Estimation of net endogenous noncarbonic acid produc­tion in humans from diet potassium and protein contents. Am J Clin Nutr 68:576-583
43. Madias NE, Adrogue HJ, Horowitz GL, Cohen JJ, Schwartz WB (1979) A redefi­nition of normal acid-base equilibrium in man: carbon dioxide as a key deter­minant of normal plasma bicarbonate concentration. Kidney Int 16:612-618
44. Kurtz I, Maher T, Hulter HN, Schambe-lan M, Sebastian A (1983) Effect of diet on plasma acid-base composition in normal humans. Kidney Int 24:670-680
45. Frassetto L, Morris RC, Jr., Sebastian A (1996) Effect of age on blood acid-base composition, in adult humans: role of age-related renal functional decline. Am J Physiol 271:1114-1122
46. Sebastian A, Harris ST, Ottaway JH, Todd KM, Morris RC, Jr. (1994) Im­proved mineral balance and skeletal metabolism in postmenopausal women treated  with  potassium  bicarbonate [see commtnts]. N Engl J Med 330: 1776-1781
47. Lindeman RD (1986) Anatomic and physiologic age changes in the kidney. Exp Gerontol 21:379-406
48. Davies  DF,  Shock  NW  (1950)  Age changes in glomerular filtration rate, effective renal plasma flow, and tubular excretory capacity in adult males. J Clin Invest 29:496-507
49. Barzel US (1995) The skeleton as an ion exchange system: implicaitons for the role of acid-base imbalance in the gen­esis of osteoporosis. J Bone Miner Res 10:1431-1436
50. Kraut JA, Mishler DR, Singer FR, Good­man WG (1986) The effects of meta­bolic acidosis on bone formation and bone resorption in the rat. Kidney Int 30:694-700
51. Lemann J, Jr., litzow JR, Lennon EJ (1966) The effects of chronic acid loads in normal man: further evidence for participation of bone mineral in the de­fense against chronic metabolic acido­sis. J Clin Invest 45:1608-1614
52. Lemann J, Jr., Lennon EJ, Goodman AD, Litzow JR, Relman AS (1965) The net balance of acid in subjects given large loads of acid or alkali. J Clin Invest 44:507-517
53. Litzow JR,. Lemann J, Jr., Lennon EJ (1967) The effect of treatment of acido­sis on calcium balance in patients with chronic azotemic renal disease. J Clin Invest 46:280-286
54. Bushinsky DA, Chabala JM, Gavrilov KL,Levi-Setti R (1999) Effects of in vivo metabolic acidosis on midcortical bone ion composition. Am J Physiol 277: F813-F819
55. Breslau NA, Brinkley L, Hill KD> Pak CYC (1988) Relationship of animal pro­tein-rich diet to kidney stone formation and calcium metabolism. J Clin En-docrinol Metab 66:140-146
56. Gafter U, Kraut JA, Lee DBN, Silis V, Walling MW, Kurokawa K, Haussler MR, Coburn JW (1980) Effect of meta­bolic acidosis on intestinal absorption of calcium and phosphorus. Am J Phys­iol 239.-G480-G484
57. Bushinsky DA, Wolbach W, Sessler NE, Mogilevsky  R,  Levi-Setti   R   (1993) Physicochemical effects of acidosis on bone calcium flux and surface ion com­position. J Bone Miner Res 8:93-102
58. Bushinsky DA, Lam BC, Nespeca R, Sessler NE, Grynpas MD (1993) De­creased bone carbonate content in re­sponse to metabolic, but not respira­tory,   acidosis.  Am   J   Physiol   265: F530-F536
59. Bushinsky DA, Lechleider RJ (1987) Mechanism of proton-induced bone calcium release: calcium carbonate dis­solution. Am J Physiol 253:F998-F1005
60. Lemann J, Jr., Litzow JR, Lennon EJ (1967) Studies of the mechanism by which chronic metabolic acidosis aug­ments urinary calcium excretion in man. J Clin Invest 46:1318-1328
61. Barzel USJowsey J (1969) The effects of chronic acid and alkali administration on bone turnover in adult rats. Clin Sci 36:517-524
62. Burnell JM (1971) Changes in bone sodium and carbonate in metabolic aci­dosis and alkalosis in the dog. J Clin In­vest 50:327-331
63. Upton PK, L’Estrange JL (1977) Effects of chronic hydrochloric and lactic acid administrations on food intake, blood acid-base balance and bone composi­tion of the rat. Quart J Exp Physiol 62:223-235
64. Newell GK,Beauchene RE (1975) Effects of dietary calcium level, acid stress, and age on renal, serum, and bone re­sponses of rats. J Nutr 105:1039-1047
65. Krieger NS, Sessler NE, Bushinsky DA (1992) Acidosis inhibits osteoblastic and stimulates osteodastic activity in vitro. Am J Physiol 262:F442-F448
66. Arnett TR, Dempster DW (1986) Effect of pH on bone resorption by rat esteo-dasts  in  vitro.  Endocrinology   119: 119-124
67. TetiA,BlairHC,SchlesingerP,GranoM, Zambonin-Zallone A, Kahn AJ, Teitel-baum SL,Hruska KA (1989) Extracellu­lar protons acidify osteodasts, reduce cytosolic calcium, and promote expres­sion of cell-matrix attachment struc­tures. J Clin Invest 84:773-780
68. Simpson DP (1983) Citrate excretion: a window on renal metabolism. Am J Physiol 244:F223-F234
69. Sakhaee K, Alpern R, Jacobson HR, Pak CYC (1991) Contrasting effects of vari­ous potassium salts on renal dtrate excretion. J Clin Endocrinol Metab 72: 396-400
70. Albright  F, Burnett CH, Parson W, Reifenstein EC, Roos A (1946) Osteo-malacia and late rickets: the various eti­ologies net in the United States with emphasis on that resulting from a spe­cific form of renal acidosis, the thera­peutic indications for each etiological sub-group, and the relationship be­tween   osteomalada  and   Milkman’s syndrome. Medicine 25399-479
71. Greenberg AJ, McNamara H, McCrory WW (1966) Metabolic balance studies in primary renal tubular acidosis: ef­fects of acidosis on external calcium and phosphorus balances. J Pediatr 69: 610-618
72. Richards P, Chamberlain MJ, Wrong OM (1972) Treatment of osteomalacia of renal tubular acidosis by sodium bi­carbonate alone. Lancet 2:994-997
73. McSherry E, Morris RC, Jr. (1978) At­tainment and maintenance of normal stature with alkali therapy in infants and children with classic renal tubular addosis. J Clin Invest 61:509-527
74. CaldasA.BroyerM.DechauxM.Klein-knecht C (1992) Primary distal renal tubular acidosis in childhood: clinical study and long-term follow-up of 28 patients. J Pediatr 121:233-241
75. Garibotto G, Russo R, Sofia A, Sala MR, Sabatino C, MoscateUi P, Deferrari G, Tizianello A  (1996) Muscle protein turnover in chronic renal failure pa­tients with metabolic acidosis or nor­mal  acid-base balance. Miner Elec­trolyte Metab 22:58-61
76. May RC, Kelly RA, Mitch WE (1986) Metabolic acidosis stimulates protein degradation in rat muscle by a gluco-corticoid-dependent mechanism. J Clin Invest 77:614-621
77. Williams B, Layward E, Walls J (1991) Skeletal muscle degradation and nitro­gen wasting in rats with chronic meta­bolic acidosis. Clin Sci 80:457-462
78. Bell JD, Margen S, Calloway DH (1969) Ketosis, weight loss, uric acid, and ni­trogen balance in obese women fed sin­gle nutrients at low caloric levels. Me­tabolism 18:193-208
79. May RC, Kelly RA, Mitch WE (1987) Mechanisms for defects in muscle pro­tein metabolism in rats with chronic uremia. Influence of metabolic atido-sis.J Clin Invest 79:1099-1103
80. Papadoyannakis NJ, Stefanidis CJ, Mc-Geown M (1984) The effect of the cor­rection of metabolic acidosis on nitro­gen and potassium balance of patients with chronic renal failure. Am ) Clin Nutr 40:423-627
81. Hannaford MC, Leiter LA, Josse RG, Goldstein MB, Marliss EB, Halperin ML (1982) Protein wasting due to acidosis of prolonged fasting. Am J Physiol 243:E251-E256
82. Gougeon-Reyburn   R,   Lariviere   F, Marliss EB (1991) Effects of bicarbon­ate supplementation on urinary min­eral excretion during very low energy diets. Am J Med Sci 302:67-74
83. Cersosimo E, Williams PE, Radosevich PM, Hoxworth BT, Lacy WW, Abumrad NN (1986) Role of glutamine in adapta­tions in nitrogen metabolism during fasting. Am J Physiol 25i:E622-E628
84. Caldas A, Fontoura M (1993) Effects of chronic metabolic acidosis (CMA) in 24-hour growth hormone secretion. J Am Soc Nephrol 4:828-828
85. BrunggerM,HulterHN,KrapfR(1997) Effect of chronic metabolic acidosis on the growth hormone/IGF-1 endocrine axis: new cause of growth hormone in-sensitivity in humans. Kidney Int 51: 216-221
86. MahlbacherK,SicuroA,GerberH,Hul- 94. ter HN, Krapf R (1999) Growth hor­mone corrects addosis-induced renal nitrogen wasting and renal phosphate 95. depletion and attenuates renal magne­sium wasting in humans. Metabolism 48:763-770
87. Frassetto L, Morris RC, Jr., Sebastian A (1997) Potassium bicarbonate reduces urinary nitrogen excretion in post- 96. menopausal women. J Clin Endocrinol Metab 82:254-259

88. Frassetto L, Morris RC, Jr., Sebastian A (1996) Potassium bicarbonate increases serum growth hormone concentrations in postmenopausal women. J Am Soc 97. Nephrol 7:1349

    89.   Alpern RJ (1995) Trade-offs in the adaptation   to  acidosis.  Kidney  Int 47:1205-1215

    90.   Alpern R J, Sakhaee S (1997) The clinical spectrum of chronic metabolic acido­sis: homeostatic mechanisms produce         98. significant morbidity. Am J Kid Dis 29: 291-302

    91.   Lemann J, Jr., Gray RW, Pleuss JA (1989) Potassium bicarbonate, but not sodium bicarbonate, reduces urinary calcium 99. excretion and improves calcium bal­ance in healthy men. Kidney Int 35: 688-695

    92.   SouciSW.FachmannW, Kraut H (1986) 100. Food Composition and Nutrition Ta­bles.    Wissenschaftliche    Verlagsge-sellschaft, Stuttgart, pp 1 -1032

    93.   Hu J-F, Zhao X-H, Parpia B, Campbell TC (1993) Dietary intakes and urinary excretion of calcium and acids: a cross-sectional study of women in China. Am J Clin Nutr 58:398-406

    Halperin ML (1982) Metabolism arid acid-base physiology. Artif Organs ]6: 357-362
    Frassetto LA, Todd KM, Morris RC, Jr., Sebastian A (2000) Worldwide inci­dence of hip fracture in elderly women: relation to consumption of animal and vegetable foods. J Gerontol A Biol Sci Med Sci 55:M585-M592 Sellmeyer DE, Stone KL, Sebastian A, Cummings SR (2001) A high ratio of dietary animal to vegetable protein in­creases the rate of bone loss and the risk of fracture in postmenopausal women. Am J Clin Nutr 73:118-122 New S, Macdonald HM, Grubb DA, Reid DM (2001) Positive association between net endogenous noncarbonic acid production (NEAP) and bone health: further support for the impor­tance of the skeleton to acid-base bal­ance. Bone 28 (Suppl 5):594 Cheema-Dhadli S, Jungas RL, Hal­perin ML (1987) Regulation of urea synthesis by acid-base balance in vivo: role of NH3 concentration. Am J Phys­iol 252:F221-F225
    Simopoulos AP (1999) Evolutionary Aspects of Nutrition and Health: Diet, Exercise, Genetics and Chronic Dis­ease. Karger, Basel, pp 1-145 Lau K, Nichols R, Tannen RL (1987) Renal excretion of divalent ions in re­sponse to chronic acidosis: evidence that systemic pH is not the controlling variable. J Lab Clin Med 109:27-33